Substituted Lactams and Their Use as Anti-Cancer Agents

ABSTRACT

This invention relates to certain substituted lactam compounds, particularly caprolactam compounds, which are useful for the treatment of cancer.

This is a continuation of U.S. application Ser. No. 10/565,700 filed on25 Jan. 2006, which is a National Phase filing of InternationalApplication No. PCT/EP2004/008284 filed on 23 Jul. 2004, which claimsbenefit under 35 U.S.C. §119(e) of U.S. Provisional Application No.60/490,415, filed on Jul. 25, 2003, the entire disclosures of which arehereby incorporated by reference.

The present invention relates to the area of therapeutic agents for thetreatment of cancer. More particularly, the present invention relates tocertain substituted lactams, pharmaceutical compositions comprising saidlactam compounds, a method of treating cancer with said lactamcompounds, and a process for preparing said lactam compounds.

BACKGROUND

Cancer is a serious health problem throughout the world. As a result, anextensive number of research endeavors has been undertaken in an effortto develop therapies appropriate to the treatment and alleviation ofcancer in humans. Research has been conducted to develop anti-canceragents effective against various types of cancer. Oftentimes,anti-cancer agents which have been developed and found effective againstcancer cells are, unfortunately, also toxic to normal cells. Thistoxicity manifests itself in weight loss, nausea, vomiting, hair loss,fatigue, itching, hallucinations, loss of appetite, and otherundesirable effects.

Additionally, conventionally used cancer treatment agent often do nothave the effectiveness desired or are not as broadly effective againstdifferent types of cancers as desired. As a result, a great need existsfor therapeutic agents which are not only more effective againstmultiple types of cancer, but which have a higher degree of selectivityfor killing cancer cells with no or minimal effect on normal healthycells. In addition, highly effective and selective anti-cancer agents,in particular, against cancers of the colon, bladder, prostate, stomach,pancreas, breast, lung, liver, brain, testis, ovary, cervix, skin,vulva, small intestine, lymph glands, and blood cells are desired.Moreover, anti-cancer activity against colon, breast, lung, pancreas,and prostate cancers as well as melanomas are particularly desiredbecause of the lack of any particular effective therapy at the presenttime.

SUMMARY

The present invention provides new anti-cancer agents which areeffective against a variety of cancer cells in particular, against allliquid and solid cancers that may arise in a subject, including cancersof the colon, bladder, prostate, stomach, pancreas, breast, lung, liver,brain, testis, ovary, cervix, skin, vulva, small intestine, lymphglands, and blood cells. More particularly, the present inventionrelates to certain substituted lactams which exhibit a high degree ofselectivity in killing cancer cells.

DETAILED DESCRIPTION

The invention relates to pharmaceutical compounds that are useful forthe treatment of cancer of the formula I:

wherein

-   n is 0, 1 or 2;-   R1 is H, X₁—(C₁₋₆) alkyl-, (C₁₋₁₂)alkylC(O)—, X₂—(C₂₋₄) alkenylene-,    X₂—(C₂₋₄) alkynylene-, X₁—(C₃₋₉)cycloalkyl-, X₂—(C₃₋₉)cycloalkene-,    X₁-aryl-, X₁-(C₃₋₇)cycloalkane-(C₁₋₆)alkylene-,    X₂—(C₃₋₇)cycloalkene-(C₁₋₆)alkylene-, or X₁-aryl-(C₁₋₆)alkylene-;-   X₁ is H, (C₁₋₁₄)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₁₄)alkyl substituted by    (C₃₋₇)cycloalkyl, —OR₁, —SR_(a), —NO₂, halo or (C₁₋₆)alkylC(O)—;    aryl, aryl-(C₁₋₁₂)alkyl-, —ORa, —SRa, —NO₂, halo,    (C₁₋₁₂)alkyl-C(O)—, mono- or di-(C₁₋₄)alkylamino,    amino(C₁₋₁₆)alkyl-, or mono- or di-(C₁₋₄)alkylamino (C₁₋₁₆)alkyl;-   X2 is H, (C₁₋₁₄)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₁₄)alkyl substituted by    (C₃₋₇)cycloalkyl, —ORa —SRa, —NO₂, halo or (C₁₋₆)alkyl-C(O)—; aryl,    aryl-(C₁₋₁₂)alkyl-, amino(C₁₋₁₆)alkyl- or mono- or    di-(C₁₋₄)alkylamino(C₁₋₁₆)alkyl;-   Ra is H, (C₁₋₁₈)alkyl, aryl, or (C₁₋₁₈)alkyl substituted by    (C₃₋₇)cycloalkyl, aryl, —OH, —O—(C₁₋₆)alkyl or halo;-   R2, R3, R4 and R5 are independently hydrogen or (C₁₋₁₈)alkyl, R5 is    also phenyl or (C₁₋₁₆)alkyl which is substituted by phenyl, wherein    there is no more than a total of 18 carbon atoms in the combined R2,    R3, R4 and R5 alkyl substituents, or R2 and R4 together or R3 and R5    together form an acetal group;-   R6 is hydrogen or (C₁₋₆) alkyl;-   R7 is H, (C₁₋₁₈)alkyl, phenyl, pyridyl, (C₁₋₁₈)alkyl substituted by    (C₃₋₇)cycloalkyl, —ORx, N₃, halo, —N(Rx)₂, Rx, —O—(C₁₋₆)alkyl,    —OC(O)—(C₁₋₁₆)alkyl or pyridyl; —Y—Rb or a substituent of formula    IIa or IIIa

wherein

-   R9 is from 0 to 3 substituents selected from (C₁₋₆)alkyl, —ORa,    —SRa, —NO₂, halo, —N₃, (C₁₋₁₂)alkylC(O)—, mono- or    di-(C₁₋₄)alkylamino, amino(C₁₋₁₆)alkyl-, mono- or    di-(C₁₋₄)alkylamino(C₁₋₁₆)alkyl, (CH₂)₀₋₂—C₅₋₇cycloalkyl,    (CH₂)₀₋₂-heterocyclic, (CH₂)₀₋₂—C₅₋₇aryl, or (CH₂)₀₋₂-heteroaryl;-   Y is a linking group selected from —(C₁₋₁₀)alkyl-,    —(C₀₋₁₀)alkylene-CO—N(Rx)-(C₀₋₁₀)alkylene-,    —(C₀₋₁₀)alkylene-N(Rx)-CO—(C₀₋₁₀)alkylene-,    —(C₀₋₁₀)alkylene-CO—O—(C₀₋₁₀)alkylene-,    —(C₁₋₁₀)alkylene-O—C(O)—(C₁₋₁₀)alkylene-,    —(C₀₋₁₀)alkylene-CO—(C₀₋₁₀)alkylene-,    —(C₀₋₁₀)alkylene-(Rx)N-CO—O—(C₀₋₁₀)alkylene-,    —(C₀₋₁₀)alkylene-O—CO—(Rx)N—(C₀₋₁₀)alkylene- or    —(C₀₋₁₈)alkylene-arylene-(C₀₋₁₈)alkylene-;-   Rx is H, (C₁₋₄)alkyl or phenyl;-   Rb is (C₁₋₁₆)alkyl or (C₁₋₁₆)alkyl which is substituted by    (C₃₋₇)cycloalkyl, —ORx, N₃, halo, —N(Rx)₂, —O—(C₁₋₆)alkyl,    —OC(O)—(C₁₋₁₆)alkyl or pyridyl;-   R8 is H, halo, —N₃, (C₁₋₁₆)alkyl, -Z-(C₁₋₁₆)alkyl, (C₁₋₁₆)alkyl    substituted by (C₃₋₇)cycloalkyl, —N(₃, —N(Rx)₂, -Z-het, —ORa or    —SRa, -Z-(C₁₋₁₆)alkyl substituted by (C₃₋₇)cycloalkyl, —N₃, —N(Rx)₂,    -Z-het, —ORa or —SRa, —O(C₁₋₁₆)alkylene-N₃,    —O(C₁₋₁₆)alkylene-N(Rx)₂, —(C₀₋₆)alkylene-OC(O)—(C₁₋₁₆)alkyl,    —(C₀₋₆)alkylene-(O)C—O—(C₁₋₁₆)alkyl,    —(C₀₋₆)alkylene-OC(O)—(C₃₋₇)cycloalkyl,    —(C₀₋₆)alkylene-(O)C—O—(C₃₋₇)cycloalkyl, pyridyl,    —OC(O)O(C₁₋₁₂)alkyl, —O—CO—X-Rz, or —O—CO—(CH₂)m-O—(CH₂)m-X-Rz    wherein X is a direct bond, (C₁₋₁₂)alkylene, (C₁₋₁₂)alkenylene or    (C₁₋₁₂)alkynylene and Rz is H, (C₃₋₉)cycloalkyl, phenyl, phenyl    substituted by one or more of chloro, methoxy, (C₁₋₁₈)alkyl or    (C₁₋₁₈)alkoxy, pyrrolyl, furanyl, thiofuranyl, indolyl,    benzofuranyl, benzothiofuranyl or pyridyl and each m is    independently a number from 0 to 13,-Z-het, —ORa, —SRa, mono- or    di-(C₁₋₄)alkylamino, amino(C₁₋₁₆)alkyl-, mono- or    di-(C₁₋₄)alkylamino(C₁₋₁₆)alkyl, -Z-Si((C₁₋₆)alkyl)₃ or a    substituent selected from the following two formulae:

-   Z is a direct bond, —(C₁₋₁₂)alkylene-, —(C₁₋₁₂)alkylene-O—,    —O—(C₁₋₁₂)alkylene-, —(C₁₋₁₂)alkylene-N(Rx)-, —N(Rx)-,    —N(Rx)-(C₁₋₁₂)alkylene-, —N(Rx)-C(O)—, —N(Rx)-C(O)—(C₁₋₁₂)alkylene-,    —(C₁₋₁₂)alkylene-N(Rx)-C(O)—,    —(C₁₋₈)alkylene-N(Rx)-C(O)—(C₁₋₈)alkylene-,    —(C₁₋₁₂)alkylene-CO—N(Rx)-, —CO—N(Rx)-(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-CO—N(Rx)-(C₁₋₈)alkylene-, —CO—N(Rx)-,    —(C₁₋₁₂)alkylene-CO—O‘3, —(C₁₋₁₂)alkylene-O—C(O)—,    —OC(O)—(C₁₋₁₂)alkylene-, —C(O)—O—(C₁₋₁₂)alkylene-,    —(C₁₋₁₂)alkylene-CO—, —(C₁₋₈)alkylene-CO—(C₁₋₈))alkylene-,    —CO—(C₁₋₁₂)alkylene-, —C(O)—, —N(Rx)-C(O)—O—,    —N(Rx)-C(O)—O—(C₁₋₁₂)alkylene-, —(C₁₋₁₂)alkylene-N(Rx)-C(O)—O—,    —(C₁₋₈)alkylene-N(Rx)-C(O)—O—(C₁₋₈)alkylene-,    —(C₁₋₁₂)alkylene-O—CO—N(Rx)-, —O—CO—N(Rx)-(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-O—CO—N(Rx)—(C₁₋₈)alkylene-, —O—CO—N(Rx)-, —O—CO—O—,    —(C₁₋₁₂)alkylene-O—CO—O—, —O—CO—O—(C₁₋₁₂)alkylene- or    —(C₁₋₈)alkylene-O—C(O)—O—(C₁₋₈)alkylene-;-   Z1 is a direct bond, —(C₁₋₁₂)alkylene-, —O—(C₁₋₁₂)alkylene-,    —N(Rx)-(C₁₋₁₂)alkylene-, —N(Rx)-C(O)—(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-N(Rx)-C(O)—(C₁₋₈)alkylene-,    —CO—N(Rx)-(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-CO—N(Rx)-(C₁₋₈)alkylene-, —OC(O)—(C₁₋₁₂)alkylene-,    —C(O)—O—(C₁₋₁₂)alkylene-, —(C₁₋₈)alkylene-CO—(C₁₋₈))alkylene-,    —CO—(C₁₋₁₂)alkylene-, —C(O)—, —N(Rx)-C(O)—O—(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-N(Rx)-C(O)—O—(C₁₋₈)alkylene-,    —O—CO—N(Rx)-(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-O—CO—N(Rx)-(C₁₋₈)alkylene-, —O—CO—O—(C₁₋₁₂)alkylene-    or —(C₁₋₈)alkylene-O—C(O)—O—(C₁₋₈)alkylene-;-   R10 is from 0 to 3 substituents selected from hydroxy, halo,    —(C₁₋₁₇)alkyl, —O—(C₁₋₁₇)alkyl, —(CH₂)₁₋₆—C₃₋₇-Cycloalkyl,    —(CH₂)₀₋₁₀-aryl or -(CH2)₀₋₁₀-het;-   het is a heterocyclic or heteroaromatic ring;-   p is 1-18;-   or a pharmaceutically acceptable salt thereof;-   with the proviso that when n is 2 and R1 is (C₁₋₆)alkyl-CH═CH— or    (C₃₋₆)cycloalkyl-CH═CH— then R7 is not H or (C₁₋₈)alkyl or R8 is not    —O—CO—X-RZ or —O—CO—(CH₂)m-O—(CH₂)m-X-RZ where X is a direct bond,    (C₁₋₁₂)alkylene, (C₁₋₁₂)alkenylene or (C₁₋₁₂)alkynylene and Rz is H,    (C₃₋₉)cycloalkyl, phenyl, phenyl substituted by one or more of    chloro, methoxy, (C₁₋₁₈)alkyl or (C₁₋₁₈)alkoxy, pyrrolyl, furanyl,    thiofuranyl, indolyl, benzofuranyl, benzothiofuranyl or pyridyl and    each m is independently a number from 0 to 13, and with the further    proviso that R8 is not —OH when n is 2, R7 is H or methyl and R₁ is    3-methylbut-1-enylene.

The present invention further also relates to compounds that are usefulfor the treatment of cancer of the formula I, wherein

-   n is 0, 1 or 2;-   R1 is X₁—(C₁₋₆) alkyl-, X₂—(C₂₋₄) alkenylene-, X₂—(C₂₋₄)    alkynylene-, X₁—(C₃₋₉)cycloalkyl-, Y₂—(C₃₋₉)cycloalkene-, X₁-aryl-,    X₁—(C₃₋₇)cycloalkane-(C₁₋₆)alkylene-,    X₂—(C₃₋₇)cycloalkene-(C₁₋₆)alkylene-, or X₁-aryl-(C₁₋₆)alkylene-;-   X₁ is H, (C₁₋₁₄)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₁₄)alkyl substituted by    (C₃₋₇)cycloalkyl, —ORa, —SRa, —NO₂, halo or (C₁₋₆)alkylC(O)-; aryl,    aryl-(C₁₋₁₂)alkyl-, —OR_(a), —SR_(a), —NO₂, halo,    (C₁₋₁₂)alkyl-C(O)-, mono- or di-(C₁₋₄)alkylamino,    amino(C₁₋₁₆)alkyl-, or mono- or di-(C₁₋₄)alkylamino(C₁₋₁₆)alkyl;-   X₂ is H, (C₁₋₁₄)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₁₄)alkyl substituted by    (C₃₋₇)cycloalkyl, —OR_(a)—SR_(a), —NO₂, halo or (C₁₋₆)alkyl-C(O)—;    aryl, aryl-(C₁₋₁₂)alkyl-, amino(C₁₋₁₆)alkyl- or mono- or    di-(C₁₋₄)alkylamino(C₁₋₁₆)alkyl;-   R_(a) is H, (C₁₋₁₈)alkyl, aryl, or (C₁₋₁₈)alkyl substituted by    (C₃₋₇)cycloalkyl, aryl, —OH, —O—(C₁₋₆)alkyl or halo;-   R₂, R₃, R₄ and R₅ are independently hydrogen or (C₁₋₁₈)alkyl, R₅ is    also phenyl or (C₁₋₁₆)alkyl which is substituted by phenyl, wherein    there is no more than a total of 18 carbon atoms in the combined R₂,    R₃, R₄ and R₅ alkyl substituents, or R₂ and R₄ together or R₃ and R₅    together form an acetal group;-   R₆ is hydrogen or (C₁₋₆) alkyl;-   R7 is H, (C₁₋₁₈)alkyl, phenyl, pyridyl, (C₁₋₁₈)alkyl substituted by    (C₃₋₇)cycloalkyl, —OR_(x), N₃, halo, —N(R_(x))₂, —O—(C₁₋₆)alkyl,    —OC(O)—(C₁₋₁₆)alkyl or pyridyl; —Y—R_(b) or a substituent of formula    IIa or IIIa

wherein

-   R9 is from 0 to 3 substituents selected from (C₁₋₆)alkyl, —OR_(a),    —SR_(a), —NO₂, halo, —N₃, (C₁₁₋₂)alkylC(O)—, mono- or    di-(C₁₋₄)alkylamino, amino(C₁₋₁₆)alkyl-, or mono- or    di-(C₁₋₄)alkylamino(C₁₋₁₆)alkyl;-   Y is a linking group selected from —(C₁₋₁₀)alkyl-,    —(C₀₋₁₀)alkylene-CO—N(R_(x))—(C₀₋₁₀)alkylene-,    —(C₀₋₁₀)alkylene-N(R_(x))—CO—(C₀₋₁₀)alkylene-,    —(C₀₋₁₀)alkylene-CO—O—(C₀₋₁₀)alkylene-,    —(C₁₋₁₀)alkylene-O—C(O)—(C₁₋₁₀)alkylene-,    —(C₀₋₁₀)alkylene-CO—(C₀₋₁₀)alkylene-,    —(C₀₋₁₀)alkylene-(R_(x))N—CO—O—(C₀₋₁₀)alkylene-,    —(C₀₋₁₀)alkylene-O—CO—(R_(x))N—(C₀₋₁₀)alkylene- or    —(C₀₋₁₈)alkylene-arylene-(C₀₋₁₈)alkylene-;-   R_(x) is H, (C₁₋₄)alkyl or phenyl;-   R_(b) is (C₁₋₁₆)alkyl or (C₁₋₁₆)alkyl which is substituted by    (C₃₋₇)cycloalkyl, —OR_(x), N₃, halo, —N(R_(x))₂, —O—(C₁₋₆)alkyl,    —OC(O)—(C₁₋₁₆)alkyl or pyridyl;-   R8 is H, halo, —N₃, (C₁₋₁₆)alkyl, -Z-(C₁₋₁₆)alkyl, (C₁₋₁₆)alkyl    substituted by (C₃₋₇)cycloalkyl, —N₃, —N(R_(x))₂, -Z-het, —OR_(a) or    —SR_(a), -Z-(C₁₋₁₆)alkyl substituted by (C3-7)cycloalkyl, —N₃,    —N(R_(x))₂, -Z-het, —OR_(a) or —SR_(a), —O(C₁₋₁₆)alkylene-N₃,    —O(C₁₋₁₆)alkylene-N(R_(x))₂, —(C₀₋₆)alkylene-OC(O)—(C₁₋₁₆)alkyl,    —(C₀₋₆)alkylene-(O)C—O—(C₁₋₁₆)alkyl,    —(C₀₋₆)alkylene-OC(O)—(C₃₋₇)cycloalkyl,    —(C₀₋₆)alkylene-(O)C—O—(C₃₋₇)cycloalkyl, pyridyl,    —OC(O)O(C₁₋₁₂)alkyl, -Z-het, —OR_(a), —SR_(a), mono- or    di-(C₁₋₄)alkylamino, amino(C,₁,₆)alkyl-, mono- or    di-(C₁₋₄)alkylamino(C₁₋₁₆)alkyl, -Z-Si((C₁₋₆)alkyl)₃ or a    substituent selected from the following two formulae:

-   Z is a direct bond, —(C₁₋₁₂)alkylene-, —(C₁₋₁₂)alkylene-O—,    —O—(C₁₋₁₂)alkylene-, —(C₁₋₁₂)alkylene-N(R_(x))—, —N(R_(x))—,    —N(R_(x))—(C₁₋₁₂)alkylene-, —N(R_(x))—C(O)—,    —N(R_(x))—C(O)—(C₁₋₁₂)alkylene-, —(C₁₋₁₂)alkylene-N(R_(x))—C(O)—,    —(C₁₋₈)alkylene-N(R_(x))—C(O)—(C₁₋₈)alkylene-,    —(C₁₋₁₂)alkylene-CO—N(R_(x))—, —CO—N(R_(x))—(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-CO—N(R_(x))—(C₁₋₈)alkylene-, —CO—N(R_(x))—,    —(C₁₋₁₂)alkylene-CO—O—, —(C₁₋₁₂)alkylene-O—C(O)—,    —OC(O)—(C₁₋₁₂)alkylene-, —C(O)—O—(C₁₋₁₂)alkylene-,    —(C₁₋₁₂)alkylene-CO—, —(C₁₋₈)alkylene-CO—(C₁₋₈))alkylene-,    —CO—(C₁₋₁₂)alkylene-, —C(O)—, —N(R_(x))—C(O)—O—,    —N(R_(x))—C(O)—O—(C₁₋₁₂)alkylene-,    —(C₁₋₁₂)alkylene-N(R_(x))—C(O)—O—,    —(C₁₋₈)alkylene-N(R_(x))—C(O)—O—(C₁₋₈)alkylene-,    —(C₁₋₁₂)alkylene-O—CO—N(R_(x))—, —O—CO—N(R_(x))—(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-O—CO—N(R_(x))—(C₁₋₈)alkylene-, —O—CO—N(R_(x))—,    —O—CO—O—, —(C₁₋₁₂)alkylene-O—CO—O—, —O—CO—O—(C₁₋₁₂)alkylene- or    —(C₁₋₈)alkylene-O—C(O)—O—(C₁₋₈)alkylene-;-   Z₁ is a direct bond, —(C₁₋₁₂)alkylene-, —O—(C₁₋₁₂)alkylene-,    —N(R_(x))—(C₁₋₁₂)alkylene-, —N(R_(x))—C(O)—(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-N(R_(x))—C(O)—(C₁₋₈)alkylene-,    —CO—N(R_(x))—(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-CO—N(R_(x))—(C₁₋₈)alkylene-,    —OC(O)—(C₁₋₁₂)alkylene-, —C(O)—O—(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-CO—(C₁₋₈))alkylene-, —CO—(C₁₋₁₂)alkylene-, —C(O)—,    —N(R_(x))—C(O)—O—(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-N(R_(x))—C(O)—O—(C₁₋₈)alkylene-,    —O—CO—N(R_(x))—(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-O—CO—N(R_(x))—(C₁₋₈)alkylene-,    —O—CO—O—(C₁₋₁₂)alkylene- or    —(C₁₋₈)alkylene-O—C(O)—O—(C₁₋₈)alkylene-;-   R10 is from 0 to 3 substituents selected from hydroxy, halo,    -(C₁l₁₇)alkyl, —O—(C₁₋₁₇)alkyl, —(CH₂)₁₋₆—C₃₋₇-cycloalkyl,    —(CH₂)₀₋₁₀-aryl or —(CH₂)₀₋₁₀-het;-   het is a heterocyclic or heteroaromatic ring;-   p is 1-18;-   or a pharmaceutically acceptable salt thereof;-   with the proviso that when n is 2 and R₁ is (C₁₋₆)alkyl-CH═CH— or    (C₃₋₆)cycloalkyl-CH═CH— then R₇ is not H or (C₁₋₈)alkyl or R₈ is not    —O—CO—X-Rz or —CO—(CH₂)_(m)—O—(CH₂)_(m)—X-R_(Z) where X is a direct    bond, (C₁₋₁₂)alkylene, (C₁₋₁₂)alkenylene or (C₁₋₁₂)alkynylene and    R_(z) is H, (C₃₋₉)cycloalkyl, phenyl, phenyl substituted by one or    more of chloro, methoxy, (C₁₋₁₈)alkyl or (C₁₋₁₈)alkoxy, pyrrolyl,    furanyl, thiofuranyl, indolyl, benzofuranyl, benzothiofuranyl or    pyridyl and each m is independently a number from 0 to 13, and with    the further proviso that R₈ is not —OH when n is 2, R₇ is H or    methyl and R₁ is 3-methylbut-1-enylene.

Interesting compounds of formula I are those wherein:

-   n is 2; and/or-   R1 is X₁—(C₁₋₆) alkyl-, X₂—(C₂₋₄) alkenylene-, X₁—(C₃₋₇)cycloalkyl-,    or X₁—(C₃₋₇)cycloalkane-(C₁₋₃)alkylene-; and/or-   X₁ is H, (C₁₋₁₂)alkyl, especially branched (C₁₋₆)alkyl;    (C₃₋₇)cycloalkyl, —(C₁₋₁₂)alkyl substituted by (C₃₋₇)cycloalkyl,    —OR_(a); —SR_(a), —NO₂, halo or (C₁₋₁₂)alkylC(O)-; aryl,    aryl-(C₁₋₁₂)alkyl- or —OR_(a); and/or-   X₂ is H, (C₁₋₁₂)alkyl, (C₃₋₇)cycloalkyl, —(C₁₋₁₂)alkyl substituted    by (C₃₋₇)cycloalkyl, —OR_(a), —SR_(a), —NO₂, halo or    (C₁₋₁₂)alkylC(O)—, aryl, aryl-(C₁₋₁₂)alkyl-; and/or-   R_(a) is H, (C₁₋₁₈)alkyl, aryl-, or (C₁₋₁₈)alkyl substituted by    (C₃₋₇)cycloalkyl or aryl;-   R₂, R₃, R₄ and R₅ are independently hydrogen or (C₁₄)alkyl, wherein    there is no more than a total of 8 carbon atoms, especially no more    than 4 carbon atoms, in the combined R₂, R₃, R₄ and R₅ alkyl    substituents; and/or-   R6 is hydrogen or (C₁₋₆) alkyl; and/or-   R7 is H, (C₁₋₈)alkyl, R_(x), (C₁₋₁₈)alkyl substituted by    (C₃₋₇)cycloalkyl, —OR_(x), N₃, halo, —N(R_(x))₂, —O—(C₁₋₆)alkyl,    —OC(O)—(C₁₋₁₆)alkyl or pyridyl; especially 3-pyridyl, or a    substituent of formula IIa or IIIa

and/or

-   R9 is from 0 to 3 substituents selected from (C₁₋₆)alkyl, —OR_(a),    —SR_(a), —NO₂, halo, or —N₃; and/or-   Y is a linking group selected from —C(O)N(R_(x))—, —CO—O—,    —(C₁₋₁₂)alkylene-CO—O—, —CO—O—(C₁₋₁₂)alkylene-,    —(C₁₋₁₀)alkylene-CO—O—(C₁₋₁₀)alkylene-,    —(C₁₋₁₀)alkylene-O—C(O)—(C₁₋₁₀)alkylene-, —CO—,    —(C₁₋₁₂)alkylene-CO—, —CO—(C₁₋₁₂)alkylene-,    —(C₁₋₁₀)alkylene-CO—(C₁₋₁₀)alkylene-, —(C₁₋₁₂)alkylene-(R_(x))N—CO—,    —(C₁₋₁₀)alkylene-(R_(x))N—CO—O—(C₁₋₁₀)alkylene-, or    —(C₀₋₁₂)alkylene-arylene-(C₀₋₁₂)alkylene-; and/or-   R_(x) is H, (C₁₋₄)alkyl or phenyl;-   R8 is —N₃, (C₁₋₁₆)alkyl, -Z-(C₁₋₁₆)alkyl, (C₁₋₁₆)alkyl substituted    by (C₃₋₇)cycloalkyl, —N₃, or —N(R_(x))₂; -Z-(C₁₋₁₆)alkyl substituted    in the alkyl portion by (C₃₋₇)cycloalkyl, —N₃, or —N(R_(x))₂,    —(C₀₋₆)alkylene-(O)C—O—(C₁₋₁₆)alkyl, or a substituent selected from    the following two formulae:

and/or

-   Z is a direct bond, —(C₁₋₁₂)alkylene-, —N(R_(x))—C(O)—,    —N(R_(x))—C(O)—(C₁₋₁₂)alkylene-, —(C₁₋₁₂)alkylene-N(R_(x))—C(O)—,    —(C₁₈)alkylene-N(R_(x))—C(O)—(C₁₋₈)alkylene-,    —(C₁₋₁₂)alkylene-CO—N(R_(x))—, —CO—N(R_(x))—(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-CO—N(R_(x))—(C₁₋₈)alkylene-, —CO—N(R_(x))—,    —C(O)—O—(C₁₋₁₂)alkylene-, —CO—(C₁₋₁₂)alkylene-, —C(O)—,    —N(R_(x))—C(O)—O—, —N(R_(x))—C(O)—O—(C₁₋₁₂)alkylene-,    —(C₁₋₁₂)alkylene-N(R_(x))—C(O)—O—,    —(C₁₋₈)alkylene-N(R_(x))—C(O)—O—(C₁₋₈)alkylene-,    —(C₁₋₁₂)alkylene-O—CO—N(R_(x))—, —O—CO—N(R_(x))—(C₁₋₁₂)alkylene-,    —(C₁₋₈)alkylene-O—CO—N(R_(x))—(C₁₋₈)alkylene- or —O—CO—N(R_(x))—;    and/or-   Z₁ is a direct bond, —(C₁₋₁₂)alkylene- or —C(O)—; and/or-   R10 is from zero to 3 substituents selected from hydroxy, halo,    —(C₁₋₁₇)alkyl, —O—(C₁₋₁₇)alkyl, —O—(C₁₋₁₇)alkyl,    —(CH₂)₁₋₆—C_(3-7 -c)ycloalkyl, —(CH₂)₀₋₁₀-aryl or —(CH₂)₀₋₁₀-het;    and/or-   het is pyridyl.

Further interesting compounds of formula (I) include those wherein

-   R1 is (C₁₋₆ alkyl)-ethenylene-; especially those wherein the alkyl    group is branched and the double bond is trans; and/or-   R₂, R₃ and R₄, independently are hydrogen or (C₁₋₄) alkyl, wherein    there is no more than a total of 4 carbon atoms in the combined R₂,    R₃, R₄ and R₅ alkyl substituents; and/or-   R₅ is (C₁₋₄)alkyl, especially methyl, and/or-   R6 is hydrogen or methyl; and/or-   R7 is H or (C₁₋₆)alkyl; and/or-   R8 is H, —N₃, (C₁₋₁₆)alkyl, -Z-(C₁₋₁₆)alkyl, (C₁ ₁₆)alkyl    substituted by (C₃₋₇)cycloalkyl, —N₃, or —N(R_(x))₂ or    -Z-(C₁₋₁₆)alkyl substituted in the alkyl portion by    (C₃₋₇)cycloalkyl, —N₃, or —N(R_(x))₂,-   R9 is (CH₂)₀₋₂—C₅₋₇ cycloalkyl, (CH₂)₀₋₂—C₅₋₇ hetero-cyclic,    (CH₂)₀₋₂—C₅₋₇ aryl, or (CH₂)₀₋₂—C₅₋₇ hetero-aryl;-   X is (C₁₋₁₂) alkylene or (C₂₋₁₂) alkenylene; and/or-   R10 is from 0 to 3 substituents selected from hydroxy, halo,    —(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl, —(CH₂)₁₋₆—C_(3-7 -c)ycloalkyl,    —(CH₂)₀₋₁₀-aryl or —(CH₂)₀₋₁₀-het; and/or-   het is pyridyl;-   especially those wherein n is 2.

Additional interesting compounds are those of formula I where

-   R1 is —CH═CH-i-propyl or —CH═CH-t-butyl, especially in the trans    geometry;-   X₂ is H;-   R₂, R₃, R₄, and R₅ independently are hydrogen or methyl;-   R6 is hydrogen;-   R7 is H or (C₁₋₃) alkyl;-   especially wherein n is 2.

Additional interesting compounds are those of formula I wherein:

-   R₁ is X₁-(C₃₋₇)-cycloalkane-(C₁₋₆)alkylene- or    X₂-(C₃₋₉)cycloalkene-;-   X₁ is hydrogen;-   X₂ is hydrogen;-   R₂, R₃, R₄ and R₅ independently are hydrogen or methyl;-   R₆ is hydrogen;-   R₇ is H or (C₁₋₃)alkyl;-   R₈ is H; and-   n is 2.

In another embodiment, the invention provides pharmaceuticalcompositions, especially for the treatment of cancer in subjects,especially human, comprising a pharmaceutically acceptable carrier ordiluent and an antitumorally effective dose of a compound of formula Iabove, or a pharmaceutically acceptable salt thereof, where possible.

In still another embodiment, the current invention provides a method fortreating cancer comprising administering to a subject, especially human,in need of such treatment a therapeutically effective amount of acompound of formula I above, or a pharmaceutically acceptable saltthereof, where possible. The effective dosage of the compounds of theinvention for such treatment may encompass a range of from about 0.01milligrams per kilogram body weight per day to about 0.02 grams perkilogram of body weight per day.

In another embodiment, the current invention relates to the use of acompound of formula I or of a pharmaceutically acceptable salt of such acompound for the preparation of a pharmaceutical composition for use inthe chemotherapy of cancer.

Furthermore, the current invention relates to the use of a compound offormula I or of a pharmaceutically acceptable salt of such a compoundfor the chemotherapy of cancer.

In the above definitions:

The alkyl groups, including any alkyl portion of a substituent, such asalkoxy, are either straight or branched chain, of which examples of thelatter include isopropyl, isobutyl, t-butyl, isopentyl, neopentyl,isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and1,1,2,2-tetramethylethyl unless otherwise noted.

The term “alkylene” as used herein refers to a straight or branchedchain consisting solely of carbon and hydrogen. Examples of “alkylene”groups include methylene, ethylene, propylene, butylene, pentylene, and3-methypentylene.

The term “alkenylene” as used herein refers to a straight or branchedchain consisting solely of carbon and hydrogen, containing at least onecarbon-carbon double bond. Examples of “alkenylene” groups includeethenylene, propenylene, butenylene, 3,3,-dimethylbut-1-enylene,3-methylbut-1-enylene, pentenylene, 3-methylpentenylene, and butadiene.

The term “alkynylene” as used herein refers to a straight or branchedchain divalent group consisting solely of carbon and hydrogen containingat least one carbon-carbon triple bond. Examples of “alkynylene” groupsinclude acetylene, propynylene, butynylene, pentynylene,3-methylpentynylene.

If R2 and R4 together or R3 and R5 together form an acetal group, R2 andR4 together or R3 and R5 together preferably form a group of the formula—C(R′)(R″)—, wherein R′ and R″ are selected independently of each otherfrom X₁-(C₁₋₆) alkyl-, X₂-(C₂₋₄) alkenyl-, X₁—(C₃₋₇)cycloalkyl-, orX₁—(C₃₋₇)cycloalkane-(C₁₋₃)alkyl-wherein X₁ is as defined herein.

The term “direct bond” as herein described refers to a single, double,or triple, covalent atomic bond which links together two moieties.

Halo is chloro, bromo, iodo or fluoro, especially chloro, bromo or iodo.

The substituent het is preferably a 3 to 9 membered aliphatic ring, suchas a 4 to 7 membered aliphatic ring, containing from one to threeheteroatoms selected from nitrogen, sulfur and oxygen, or het is a 5 to7 member aromatic ring containing one or more heteroatoms, for examplefrom 1 to 4 heteroatoms, selected from N, O and S, or het is a bicyclicand tricyclic fused ring system where each ring can independently be 5or 6 membered and contain one or more heteroatoms, for example, 1, 2, 3,or 4 heteroatoms, chosen from O, N or S such that the fused ring systemis aromatic. Examples of suitable het substituents include pyrrolidyl,tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl,tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane,1,4-oxazepane, 1,4-oxathiapane, furyl, thienyl, pyrrole, pyrazole,triazole, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, pyrazine,quinoline, isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine,indole, benzofuran, benzothiofuran, benzindole, benzoxazole, andpyrroloquinoline. Het is preferably pyridyl.

In the instance where het is a nitrogen containing ring, N-substitutedcompounds are included. Suitable N-substituents include (C₁₋₁₄)alkyl,such as N-methyl or N-ethyl, —C(O)C₁₋₁₂alkyl, such as methylamido orethylamido, —C(O)—O—(C₁₋₁₄)alkyl, such as carbomethoxy or carboethoxy,or phenyl.

het also includes the above rings with substitution on one or morecarbons. Suitable C-substituents include (C₁₋₁₄)alkyl, such as methyl orethyl, —OR_(a), such as methoxy and ethoxy, —SR_(a), halo, —N(R_(x))₂and the like.

Aryl includes phenyl and naphthyl substituents.

A “heteroaryl” group is mono-, bi- or tri-cyclic, and comprises 3-24,preferably 4-16 ring atoms, and is most preferably mono-cycliccomprising 5-7 ring atoms, wherein at least one or more, preferably oneto four ring carbons are replaced by a heteroatom selected from O, N orS such as azirinyl, imidazolyl, thienyl, furyl, indolyl, pyranyl,thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, 2H-pyrrolyl,pyrrolyI, benzimidazolyl, pyrazolyl, pyrazinyl, thiazolyl, isothiazolyl,dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, benzimidazolyl,benzothiazolyl and benzo[1,2,5]thiadiazolyl, thiacumaryl, indazolyl,triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl,phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, cinnolinyl,pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl,phenoxazinyl, chromenyl, isochromanyl and chromanyl, each of theseradicals being unsubstituted or substituted by one to two substituents.

“Heterocyclic” refers to a heterocyclic radical containing 1-4heteroatoms selected from nitrogen, oxygen and sulfur (e.g. piperazinyl,lower alkyl-piperazinyl, azetidinyl, pyrrolidinyl, piperidino,morpholinyl, imidazolinyl). The heterocyclic radical is preferablyunsaturated, saturated or partially saturated in the bonding ring; has3-24, more preferably 4-16 ring atoms, wherein at least in the bondingring one or more, preferably 1-4, especially one or two carbon ringatoms are replaced by a heteroatom selected from the group consisting ofnitrogen, oxygen and sulfur, the bonding ring preferably having 4-12,especially 4-7 ring atoms; the heterocyclic radical is unsubstituted orsubstituted by one or more, especially 1-4 substituents and isespecially selected from the group consisting of indoly,tetrahydrofuranyl, benzofuranyl, thienyl, pyridyl, imidazolinyl,morpholinyl, thiomorpholinyl, piperazinyl, piperidino, piperidyl,pyrrolidinyl, oxiranyl, 1,2-oxathiolanyl, pyrrolinyl, imidazolidinyl,pyrazolidinyl and azetidinyl, with piperazinyl being especiallypreferred.

In view of the close relationship between the novel compounds in freeform and in the form of their salts, including those salts that can beused as intermediates, for example in the purification or identificationof the novel compounds, hereinbefore and hereinafter any reference tothe free compounds is to be understood as referring also to thecorresponding salts, as appropriate and expedient.

Salts are especially the pharmaceutically acceptable salts of compoundsof formula I.

Salts of the compounds of formula I may be pharmaceutically acceptableacid or base addition salts with organic or inorganic acids or bases.Although the preferred acid addition salts are those of hydrochloric andmethanesulfonic acid, for example, salts of sulfuric, phosphoric,citric, fumaric, maleic, benzoic, benzenesulfonic, succinic, tartaric,lactic and acetic acid may also be utilized.

Preferably, R₂, R₃, R₄ and R₅ are in the relative stereochemicalconformation to each other depicted in stereochemical formulae Ia andIb:

The lactams of formula I may be prepared as depicted below:

where each of R1, R₅, R₇ and R8 is as defined above.

As to the individual steps, Step A involves the acylation of anaminolactam of formula VI with a lactone compound of formula VII toobtain a diamide compound of formula VIII. The acylation is conducted ina polar, organic solvent, preferably a protic polar solvent such asisopropanol, at a temperature slightly below or at the refluxtemperature of the solvent employed for a period of between 4 and 48hours.

Alternatively, the acylation of an aminolactam of formula VI, or an acidaddition salt thereof, with the lactone compound of formula VII in StepA may be carried out with in the presence of: 1) a weak base, preferablya carboxylate salt such as sodium 2-ethylhexanoate, and 2) a polar,organic solvent, preferably an ether such as tetrahydrofuran, at atemperature of between 0° C. and 50° C., preferably at 25° C., for aperiod of between 1 hour and 7 days, preferably for 20 hours.

Step B concerns the hydrolysis of the 1,3-dioxane group common to adiamide compound of formula VIII, to obtain a substituted lactamcompound of formula I. The hydrolysis is typically carried out bydissolving the diamide in a mixture of solvents consisting of 1) aprotic acid, preferably an organic acid such as trifluoroacetic acid, 2)a protic solvent, preferably water, and 3) an inert organic solvent,preferably a cyclic ether such as tetrahydrofuran, at a temperature ofbetween 0° C. and 25° C. for a period of between 5 minutes and 2 hours.

Alternatively, the diamide compounds of formula VIIIa may be preparedaccording to the following 3-step reaction scheme:

where R₁, R₅, and R₇ are as defined above, R₁₂ is an appropriatesubstituent based on the definition of R8 above, and P₂ is an alcoholprotective group. Preferably, P₂ is a silyl group such astert-butyldimethylsilyl.

As to the individual steps, Step 1 involves the acylation of anaminolactam of formula IX with a lactone compound of formula VII toobtain a diamide compound of formula X. The acylation is conducted inthe presence of a base, preferably an alkylamine base such asdiisopropylethylamine, and a polar, organic solvent, preferably a proticpolar solvent such as isopropanol, at a temperature slightly below or atthe reflux temperature of the solvent employed for a period of between 4and 48 hours.

Step 2 concerns the hydrolysis of the group P₂ common to a diamidecompound of formula X to obtain a hydroxylactam compound of formula XI.The hydrolysis is typically carried out in the presence of fluoride,preferably a fluoride salt such as tetrabutyl-ammonium fluoride, and aninert organic solvent, preferably a cyclic ether such astetrahydrofuran, at a temperature of between 0° C. and 25° C. for aperiod of between 5 minutes and 2 hours.

Step 3 concerns the acylation of a hydroxylactam compound of formula XIby reacting it with an acid chloride of formula R₁₂COCl where R₁₂, isdefined above, to obtain a diamide compound of formula VIIIa. Theacylation is conducted in the presence of a base, preferably analkylamine base such as triethylamine, and an inert organic solvent,preferably a chlorinated alkane such as dichloromethane, at atemperature of between −78° C. and 25° C. for a period of between 1 and24 hours.

Alternatively, the acylation of a hydroxylactam compound of formula XIin Step 3 may be carried out with a carboxylic acid of formula R₁₂COClwhere R₁₂, is defined above, in the presence of a carboxylic acidcoupling reagent, preferably a diimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and asuitable activating agent common to diimide coupling reactions,preferably a substituted pyridine such a 4-dimethylaminopyridine, and aninert organic solvent, preferably a chlorinated alkane such asdichloromethane, at a temperature of between −78° C. and 25° C. for aperiod of between 1 and 24 hours.

The aminolactam compounds of formula la may be prepared as depictedbelow:

where each R1, R₅, R₇ and R₁₂ is as defined above, and P₁ is acarbonyl-containing group. Preferably, P₁ is alkoxycarbonyl such ast-butyloxycarbonyl. P₂ is an alcohol protective group. Preferably, P₂ isa silyl group such as tert-butyldimethylsilyl.

As to the individual steps, Step 1a involves the cyclization ofhydroxylysine (or any salt or hydrate preparation thereof) XII to obtainhydroxycyclolysine XIII. The cyclization is typically carried out in thepresence of a coupling reagent, preferably a diimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and asuitable activating agent common to diimide coupling reactions,preferably an N-hydroxy compound such as 1-hydroxybenztriazole hydrate,and a base, preferably an alkylamine base such as triethylamine, and apolar organic solvent, preferably an amide such asN,N-dimethylformamide, at a temperature of between 0° C. and 40° C. fora period of between 12 and 72 hours.

Step 1b involves the N-acylation of hydroxycyclolysine XIII to obtain anN-acylhydroxycyclolysine compound of formula XIV. The acylating agent istypically an acid chloride or an anhydride. When P₁ ist-butyloxycarbonyl, the acylating agent is di-tert-butyldicarbonate. Thereaction is carried out in the presence of a base, preferably analkylamine base such as triethylamine, and a polar organic solvent,preferably an amide such as N,N-dimethylformamide, at a temperature ofbetween 0° C. and 40° C. for a period of between 1 and 24 hours.

Step 1c involves the O-silylation of an N-acylhydroxycyclolysinecompound of formula XIV to obtain a silyl ether compound of formula XV.The silylating agent is typically a silyl chloride ortrifluoromethanesulfonate. When P₂ is tert-butyldimethylsilyl, thesilylating agent is tert-butyldimethylsilylchloride. The reaction iscarried out in the presence of a base, preferably a mild base such asimidazole, and a polar organic solvent, preferably an amide such asN,N-dimethylformamide, at a temperature of between 0° C. and 40° C. fora period of between 1 and 24 hours.

Step 1d involves the N-alkylation of a silyl ether compound of formulaXV with an alkyl (defined as R₇ above) halide or sulfonate to obtain anN-alkyl lactam compound of formula XVI. The alkylation is conducted inthe presence of a strong base, preferably an alkali metal amide such assodium bis(trimethylsilyl)amide, and an inert organic solvent,preferably a cyclic ether such as tetrahydrofuran, at a temperature ofbetween −100° C. and 25° C. for a period of between 5 minutes and 2hours.

Step 1e concerns the hydrolysis of the group P₁ on an N-alkyl lactamcompound of formula XVI. The hydrolysis is typically carried out in thepresence of a protic acid, preferably an organic acid such astrifluoroacetic acid, hydrogen or a silyl halide, preferably a silyliodide such as trimethylsilyl iodide, and an inert organic solvent,preferably a chlorinated alkane such as dichloromethane, at atemperature of between −100° C. and 25° C. for a period of between 1minute and 2 hours.

Step 1f involves the acylation of an aminolactam of formula XVII with alactone compound of formula VII to obtain a diamide compound of formulaX. The acylation is conducted in the presence of a base, preferably analkylamine base such as diisopropylethylamine, and a polar, organicsolvent, preferably a protic polar solvent such as isopropanol, at atemperature slightly below or at the reflux temperature of the solventemployed for a period of between 4 and 48 hours.

Step 1g concerns the hydrolysis of the group P₂ common to an N-alkyllactam compound of formula X, to obtain a hydroxylactam compound offormula XI. The hydrolysis is typically carried out in the presence offluoride, preferably a fluoride salt such as tetrabutylammoniumfluoride, and an inert organic solvent, preferably a cyclic ether suchas tetrahydrofuran, at a temperature of between 0° C. and 25° C. for aperiod of between 5 minutes and 6 hours.

Step 1h concerns the acylation of a hydroxylactam compound of formula XIby reacting it with an acid chloride of formula R₁₂COCl where R₁₂, isdefined above, to obtain a diamide compound of formula VIII. Theacylation is conducted in the presence of a base, preferably analkylamine base such as triethylamine, and an inert organic solvent,preferably a chlorinated alkane such as dichloromethane, at atemperature of between −78° C. and 25° C. for a period of between 1 and24 hours.

Step 1i concerns the hydrolysis of the 1,3-dioxane group of compoundformula VIII, to obtain a substituted lactam compound of formula I. Thehydrolysis is typically carried out by dissolving the diamide in amixture of solvents consisting of 1) a protic acid, preferably anorganic acid such as trifluoroacetic acid, 2) a protic solvent,preferably water, and 3) an inert organic solvent, preferably a cyclicether such as tetrahydrofuran, at a temperature of between 0° C. and 25°C. for a period of between 5 minutes and 2 hours.

Alternatively, the acylation of a hydroxylactam compound of formula XIin Step 1h may be carried out with a carboxylic acid of formula R₁₂COOHwhere R₁₂, is defined, in the presence of a carboxylic acid couplingreagent, preferably a diimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and asuitable activating agent common to diimide coupling reactions,preferably a substituted pyridine such a 4-dimethylaminopyridine, and aninert organic solvent, preferably a chlorinated alkane such asdichloromethane, at a temperature of between −78° C. and 25° C. for aperiod of between 1 and 24 hours.

The aminolactam compounds of formula IIb may be prepared as depictedbelow:

R₁₄ is a leaving group.

-   where each R1, R₅, R₇ and R₁₂ is as defined above, and P₁ is a    carbonyl-containing group.    -   Preferably, P₁ is alkoxycarbonyl such as t-butyloxycarbonyl. P₂        is an alcohol protective group. Preferably, P₂ is a silyl group        such as tert-butyldimethylsilyl.

Step 2a concerns the hydrolysis of the group P2 common to an N-alkyllactam compound of formula XVI, to obtain a hydroxylactam compound offormula XVII. The hydrolysis is typically carried out in the presence offluoride, preferably a fluoride salt such as tetrabutylammoniumfluoride, and an inert organic solvent, preferably a cyclic ether suchas tetrahydrofuran, at a temperature of between 0° C. and 25° C. for aperiod of between 5 minutes and 6 hours.

Step 2b involves the O-alkylation of a compound of formula XVII with analkyl (defined as R12 above) halide or sulfonate to obtain an O-alkyllactam compound of formula XVI. The alkylation is conducted in thepresence of a strong base, preferably an alkali metal amide such assodium bis(trimethylsilyl)amide, and an inert organic solvent,preferably a cyclic ether such as tetrahydrofuran, at a temperature ofbetween −100° C. and 25° C. for a period of between 5 minutes and 6hours.

Step 2c concerns the hydrolysis of the group P1 on an N-alkyl lactamcompound of formula XVIII. The hydrolysis is typically carried out inthe presence of a protic acid, preferably an organic acid such astrifluoroacetic acid, hydrogen or a silyl halide, preferably a silyliodide such as trimethylsilyl iodide, and an inert organic solvent,preferably a chlorinated alkane such as dichloromethane, at atemperature of between −100° C. and 25° C. for a period of between 1minute and 2 hours.

Step 2d involves the acylation of an aminolactam of formula XIX with alactone compound of formula VII to obtain a diamide compound of formulaXX. The acylation is conducted in the presence of a base, preferably analkylamine base such as diisopropylethylamine, and a polar, organicsolvent, preferably a protic polar solvent such as isopropanol, at atemperature slightly below or at the reflux temperature of the solventemployed for a period of between 4 and 48 hours.

Step 2e concerns the hydrolysis of the 1,3-dioxane group of compoundformula XX, to obtain a substituted lactam compound of formula I. Thehydrolysis is typically carried out by dissolving the diamide in amixture of solvents consisting of 1) a protic acid, preferably anorganic acid such as trifluoroacetic acid, 2) a protic solvent,preferably water, and 3) an inert organic solvent, preferably a cyclicether such as tetrahydrofuran, at a temperature of between 0° C. and 25°C. for a period of between 5 minutes and 2 hours.

The aminolactam compounds of formula IIc may be prepared as depictedbelow:

where each R1, R₅, R7 is as defined above, R13 is an appropriatesubstituent based on the

Preferably, P₁ is alkoxycarbonyl such as t-butyloxycarbonyl.

Step 3a involves the substitution of the hydroxy group of the compoundof formula XVII for a heteroatom (defined as Y above) preferably withinversion of configuration and most preferably by a Mitsunobu typereaction (reference) involving a trialkyl or triaryl substitutedphosphine, an azodicarboxylate diester and a nucleophile source such asdiphenylphosphoryl azide. Alternatively the hydroxy group can beconverted to a sulfonate or halide suitable for displacement.

Step 3b concerns the hydrolysis of the group P₁ on an N-alkyl lactamcompound of formula XXI. The hydrolysis is typically carried out in thepresence of a protic acid, preferably an organic acid such astrifluoroacetic acid, hydrogen or a silyl halide, preferably a silyliodide such as trimethylsilyl iodide, and an inert organic solvent,preferably a chlorinated alkane such as dichloromethane, at atemperature of between −100° C. and 25° C. for a period of between 1minute and 2 hours.

Step 3c involves the acylation of an aminolactam of formula XXII with alactone compound of formula VII to obtain a diamide compound of formulaXXIII. The acylation is conducted in the presence of a base, preferablyan alkylamine base such as diisopropylethylamine, and a polar, organicsolvent, preferably a protic polar solvent such as isopropanol, at atemperature slightly below or at the reflux temperature of the solventemployed for a period of between 4 and 48 hours.

Step 3d concerns the hydrolysis of the 1,3-dioxane group of compoundformula XXIII, to obtain a substituted lactam compound of formula I. Thehydrolysis is typically carried out by dissolving the diamide in amixture of solvents consisting of 1) a protic acid, preferably anorganic acid such as trifluoroacetic acid, 2) a protic solvent,preferably water, and 3) an inert organic solvent, preferably a cyclicether such as tetrahydrofuran, at a temperature of between 0° C. and 25°C. for a period of between 5 minutes and 2 hours.

The aminolactam compounds of formula lid may be prepared as depictedbelow:

where each R1, R₅, and R₇ is as defined above, and P₁ is acarbonyl-containing group.

Preferably, P₁ is alkoxycarbonyl such as t-butyloxycarbonyl.

Step 4a involves the N-acylation of cyclolysine XXIV to obtain anN-acylcyclolysine compound of formula XXV. The acylating agent istypically an acid chloride or an anhydride. When P₁ ist-butyloxycarbonyl, the acylating agent is di-tert-butyldicarbonate. Thereaction is carried out in the presence of a base, preferably analkylamine base such as triethylamine, and a polar organic solvent,preferably an amide such as N,N-dimethylformamide, at a temperature ofbetween 0° C. and 40° C. for a period of between 1 and 24 hours.

Step 4b involves the N-alkylation of an N-acylcyclolysine compound offormula XXV with an alkyl (defined as R₇ above) halide or sulfonate toobtain an N-alkyl lactam compound of formula XXVI. The alkylation isconducted in the presence of a strong base, preferably an alkali metalamide such as sodium bis(trimethylsilyl)amide, and an inert organicsolvent, preferably a cyclic ether such as tetrahydrofuran, at atemperature of between −100° C. and 25° C. for a period of between 5minutes and 2 hours.

Step 4c concerns the hydrolysis of the group P₁ on an N-alkyl lactamcompound of formula XXVI, The hydrolysis is typically carried out in thepresence of a protic acid, preferably an organic acid such astrifluoroacetic acid, hydrogen or a silyl halide, preferably a silyliodide such as trimethylsilyl iodide, and an inert organic solvent,preferably a chlorinated alkane such as dichloromethane, at atemperature of between −100° C. and 25° C. for a period of between 1minute and 2 hours.

Step 4d involves the acylation of an aminolactam of formula XVII with alactone compound of formula XXVII to obtain a diamide compound offormula XXIX. The acylation is conducted in the presence of a base,preferably an alkylamine base such as diisopropylethylamine, and apolar, organic solvent, preferably a protic polar solvent such asisopropanol, at a temperature slightly below or at the refluxtemperature of the solvent employed for a period of between 4 and 48hours.

Step 4e concerns the hydrolysis of the 1,3-dioxane group of compoundformula XXIX, to obtain a substituted lactam compound of formula Id. Thehydrolysis is typically carried out by dissolving the diamide in amixture of solvents consisting of 1) a protic acid, preferably anorganic acid such as trifluoroacetic acid, 2) a protic solvent,preferably water, and 3) an inert organic solvent, preferably a cyclicether such as tetrahydrofuran, at a temperature of between 0° C. and 25°C. for a period of between 5 minutes and 2 hours.

The lactone compounds of formula VII may be prepared as depicted below:

where R1 and R₅ are as defined above.

As to the individual steps, Step 5a involves the diketalization ofpolyhydroxylated lactone of formula XXX with acetone to obtainbis(acetonide) XXXI. The diketalization is conducted in acetone assolvent using a catalyst such as iodine at a temperature of between 0°C. and the reflux temperature for a period of between 2 and 48 hours.

Step 5b involves the alkylation of bis(acetonide) XXXI with analkylating agent such as an alkyl (defined as R₅ above) halide,sulfonate or sulfate ester to obtain the ether XXXII. The alkylation isconducted in the presence of water and a base, preferably a metal oxidesuch as silver oxide, and an inert organic solvent, preferably achlorinated alkane such as dichloromethane, at a temperature of between0° C. and the reflux temperature for a period of between 12 hours and 7days.

Step 5c involves the hydrolysis of alkyl ether XXXII to obtain thedihydroxy compound of formula XXXIII. The hydrolysis is conducted in thepresence of water and a protic acid, preferably a carboxylic acid suchas acetic acid, at a temperature of between 5° C. and 35 C for a periodof between 1 and 24 hours.

Step 5d involves the oxidative cleavage of dihydroxy compound XXXIII toobtain the aldehyde XXXIV. The reaction is conducted in the presence ofan oxidant, preferably a periodate salt such as sodium periodate, in aprotic solvent, preferably an alkanol such as methanol, at a temperatureof between 0° C. and 25° C. for a period of between 10 minutes and 4hours.

Step 5e involves the olefination of aldehyde XXXIV to obtain a lactonecompound of formula VII. The olefination is conducted in the presence ofan organometallic compound, preferably an organochromium compound suchas the transient species generated from chromium(II)chloride and adiiodoalkane (defined as R1CHl2 where R1 is as defined above), in thepresence of a solvent mixture consisting of 1) a polar organic solvent,preferably an amide such as N,N-dimethylformamide, and 2) an inertorganic solvent, preferably a cyclic ether such as tetrahydrofuran, at atemperature of between −80° C. and 25° C. for a period of between 5minutes and 4 hours.

Alternatively the lactone compounds of formula VIIa may be prepared asdepicted below:

where R₅ is defined above and R′ is C₍₁₋₆₎ alkyl

Step 6a involves the conversion of XXXIII to an ortho ester XXXV by acidcatalyzed transesterification with an alkyl orthoester, preferablytriethylorthoformate and p-toluenesulfonic acid. The reaction can be runwith excess alkyl orthoester as the solvent or an inert organic solventmay be used at a temperature of between 20° C. and 80° C. for a periodbetween 1 and 24 hours.

Step 6b involves the elimination of the orthoester XXXV to give alkeneVIIa. The reaction is conducted in an organic acid anhydride, preferablyacetic anhydride at a temperature of 20° C. and 100° C. for a periodbetween 1 and 24 hours.

Alternatively the lactams of formula I may be prepared as depictedbelow:

where each R1, R₅, R₇, R₉, and X are defined above, R″ is a C₍₃₋₉₎branched alkyl or phenyl substituted C₍₁₋₃₎ alkyl, preferably benzyl andR′″ is a C₍₁₋₆₎ alkyl, preferably ethyl. P₂ and P₃ are alcoholprotective groups, preferably silyl groups such astert-butyldimethylsilyl and trimethylsilyl respectively. P₄ is analcohol protective group, preferably benzyl or 2-naphthlmethyl ethers.

Step 7a involves an Evans type aldol condensation of oxyimide XXXVI withan aldehyde to give XXXVII. The reaction is conducted in the presence ofa Lewis acid, preferably diethylborontriflate and an organic base,preferably diisopropylethylamine in an inert organic solvent such asCH2Cl2 at a temperature of between −100° C. and 0° C. for a period of1-24 hours.

Step 7b involves the O-silylation of compound XXXVII to obtain a silylether compound of formula XXXVIII. The silylating agent is typically asilyl chloride or trifluoromethanesulfonate. When P2 istert-butyldimethylsilyl, the silylating agent istert-butyldimethylsilylchloride. The reaction is carried out in thepresence of a base, preferably a mild base such as imidazole, and apolar organic solvent, preferably an amide such asN,N-dimethylformamide, at a temperature of between 0° C. and 40° C. fora period of between 1 and 24 hours.

Step 7c involves the formation of thioester XXXIX from XXXVIII byreaction with an alkali metal salt of a thioether, preferably LiSEt, inan inert solvent, preferably THF, at a temperature of between −100° C.and 0° C. for a period of 1-24 hours.

Step7d involves conversion of thioester XXXIX to the aldehyde XL byreduction with a metal hydride, preferably diisobutylaluminum hydride,in an inert solvent, preferably CH2Cl2, at a temperature of between−100° C. and 0° C. for a period of 10 minutes to 1 hour.

Step 7e involves a Gennari type coupling of aldehyde XL with athiovinylether to give the thioester XLI. The reaction is conducted inthe presence of a Lewis acid, preferably SnCl4, in an inert solvent,preferably a mixture of CH2Cl2 and heptane, at a temperature of between−100° C. and 0° C. for a period of 1-24 hours.

Step 7f involves the acylation of thioester XLI with amine VI to givediamide XLII. The reaction is conducted in an inert solvent, preferablydioxane, at a temperature of between room temperature and 100° C. for aperiod of 1-48 hours.

Step 7g involves the deprotection of diamide XLII to give compound I.The method employed is dependant on the P2 and P5 groups utilized,preferably when P2 is tert-butyldimethylsilyl and P4 is 2-naphthlmethylether a two step procedure is employed using DDQ in a mixture of wetCH3OH and CH2Cl2 followed by treatment with tetrabutylammonium fluoridein THF to give compound I.

The following specific examples are intended to further illustrate, butnot limit, the invention.

EXAMPLES Example 1 Tetradecanoic acid(3R,6S)-7-oxo-1-pyridin-3-ylmethyl-6-((2R,3R,4S,5R)-(E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enoylamino)-azepan-3-ylester

a) Preparation of 3,5:6,7-bis-O-(1-methylethylidene)-α-D-glucoheptonicγ-lactone

α-D-Glucoheptonic y-lactone (500 g, 2.4 mol) is added into 9 L ofacetone in a 5 gal plastic drum. The mixture is agitated mechanicallyuntil most of the solid dissolved (15-20 min). Iodine (60 g, 0.236 mol)is added portion wise into the lactone solution over 5-10 min. Theresulting mixture is stirred overnight. A saturated solution of Na₂S₂O₃(1.3 L) is added to the iodine solution to quench the reaction. Theresulting solution is concentrated to about half of its original volumein vacuum, and brine solution (5 L) is added. The resulting mixture isextracted with 3×1.2 L EtOAc. All organic layers are combined andevaporated to dryness. The solid is slurried with a mixture of ether andhexane (3:7), and filtered. The filter cake is washed with Et₂O (50 mL)and air dried, giving 599 g of the desired compound as a white powder(86.5%): ¹H NMR (CDCl₃) δ 4.62 (m, 1H), 4.50 (m, 1H), 4.35 (m, 2H), 4.07(m, 1H), 3.93 (m, 1H), 3.82 (dd, 1H), 3.08 (d, 1H), 1.51 (s, 3H), 1.44(s, 3H), 1.39 (s, 3H), 1.35 (s, 3H); ¹³C NMR (CDCl₃) δ 174.4, 109.4,98.6, 72.8, 71.4, 69.3, 68.4, 67.8, 66.7, 28.6, 26.7, 24.6, 19.3.

b) Preparation of2-O-methyl-3,5:6,7-bis-O-(1-methylethylidene)-α-D-glucoheptonicγ-lactone

3,5:6,7-bis-O-(1-methylethylidene)-α-D-glucoheptonic γ-lactone (719 g,2.49 mol) is added into 4.5 L of CH₂Cl₂ in a 5 gal plastic drum. Themixture is stirred under N₂. Iodomethane (2500 g, 17.6 mol) is addedimmediately followed by addition of silver(I) oxide (1750 g, 7.58 mol).Water (30 mL) is added to the reaction mixture. Ice bath is used tomaintain the reaction temperature at 15-30° C. The reaction is stirredin the absence of light for 18 h. After diluting the reaction mixturewith 1.5 L of CH₂Cl₂, the solid is filtered and washed with anadditional 2.2 L of CH₂Cl₂. The undesired solid is discarded and thefiltrate is evaporated to dryness. The residue is slurried in Et₂O (1.5L), filtered, and dried to give 618 g product (82%): ¹H NMR (CDCl₃) δ4.75 (m, 1H), 4.33 (m, 1H), 4.29 (m, 1H), 4.15 (m, 1H), 4.07 (m, 1H),3.96 (dd, 1H), 3.83 (dd, 1H), 3.65 (s, 3H), 1.57 (s, 3H), 1.42 (s, 6H),1.35 (s, 3H); ¹³C NMR (CDCl₃) δ 172.5, 109.6, 98.5, 79.0, 73.1, 69.5,68.6, 67.5, 66.9, 59.1, 28.9, 26.9, 24.9, 19.4.

c) Preparation of2-O-Methyl-3,5-O-(1-methylethylidene)-α-D-glucoheptonic γ-lactone

2-O-methyl-3,5:6,7-bis-O-(1-methylethylidene)-α-D-glucoheptonicγ-lactone (618 g, 2.05 mol) is dissolved in 8 L of a mixture of aceticacid and water (1:1) over 30 min. The solution is stirred at ambienttemperature overnight. The solution is evaporated to dryness in vacuum.The solid is slurried in 3-5 L of hot acetone and filtered. After ovendrying at 20-30° C., 363 g of the desired compound is obtained (67.6%).¹H NMR(CDCL₃): δ 4.92 (d, 1 H), 4.80 (m, 1H), 4.47 (d, 1H), 4.42 (t,1H), 4.39 (m, 1H), 3.95 (dd, 1H), 3.75 (m, 2H), 3.4 (s, 3H), 2.5 (m,1H), 1.42 (s, 3H), 1.22 (s, 3H).

d) Preparation of 2,4-O-(1-methylethylidene)-5-O-methyl-L-glucuronicγ-lactone

2-O-Methyl-3,5-O-(1-methylethylidene)-α-D-glucoheptonic γ-lactone (200g, 0.76 mol) is dissolved into a 1:1 mixture of methanol and water (3.6L). The stirred mixture is cooled in an ice water bath to about 8° C.Solid NalO₄ (213 g, 0.98 mol) is added portion wise. Reaction iscomplete within 40 min as indicated by thin layer chromatography (TLC)(silica gel, 5% methanol, 15% EtOAc in CH₂Cl₂). Solid NaCI is added intothe reaction mixture to saturate the methanolic solution. The solid isfiltered and washed with 2 L CH₂Cl₂. The filtrate is extracted with7×500 mL CH₂Cl₂. Combined organic layers are dried over Na₂SO₄, filteredand concentrated to a syrup, which formed a precipitate upon addition ofhexane. The solid is filtered and rinsed with Et₂O. A portion of thecrude product (50 g) is dissolved in 3 L CHCl₃ and heated to reflux.After rotary evaporation of 2.1 L of CHCl₃ at atmospheric pressure(methanol is driven out of the system by co-evaporation with CHCl₃) theresidue is evaporated to dryness. 44 g of the desired product isobtained as a solid after drying in vacuum overnight. ¹H NMR (CDCl3): δ9.60 (s, 1H), 4.78 (m, 1H), 4.42 (s, 2H), 4.15 (dd, 1H), 3.65 (s, 3H),1.58 (s, 3H), 1.55 (s, 3H); ¹³C NMR (CDCl₃) δ 198.8, 171.9, 99.0, 78.4,74.4, 72.9, 68.4, 67.4, 59.2, 28.7, 19.0.

e) Preparation of (6E)-6,7,8,9-tetradeoxy-8,8-dimethyl-2-O-methyl-3,5-O-(1-methylethylidene)-gulo-non-6-enonicacid lactone

Into a 2 L round bottom flask, is added CrCl₂ (50 g, 41 mmol ),anhydrous THF (750 mL), and DMF (32 mL). The mixture is stirred under N₂for 1 h. A solution of2,4-O-(1-methylethylidene)-5-O-methyl-L-glucuronic γ-lactone (12 g, 50mmol), 1,1-diiodo-2,2-dimethylpropane (15 mL), and 500 mL of anhydrousTHF is added slowly into the reaction mixture. After the addition, thereaction mixture is stirred at ambient temperature for 1.5 h. Thereaction is quenched with saturated aqueous NH₄Cl. The residue ispartitioned with EtOAc/water and chromatographed (5% EtOAc—CH₂Cl₂) togive 9 g (63%) of the desired compound as a white crystalline solid:¹HNMR (CDCl₃) δ 5.82 (d, 1H), 5.58 (q, 1H), 4.71 (m, 1H), 4.46 (m, 1H),4.10 (dd, 1H), 4.0 (m, 1H), 3.66 (s, 3H), 1.58 (s, 3H), 1.53 (s, 3H),1.07 (s, 9H); ¹³C NMR (CDCl₃) δ 172.5, 147.0, 120.2, 98.7, 79.1, 71.9,70.3, 67.6, 59.2, 33.2, 29.3, 19.3.

Preparation of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one

In a 1 L flask (5R)-5-hydroxy-L-lysine (10 g, 0.040 mol),1-hydroxybenzotriazole hydrate (8.2 g, 0.060 mol) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide-HCl (11.6 g, 0.060 mol)are added to 500 mL DMF with stirring. After 0.5 h triethylamine (16.8mL, 0.120 mol) is added. The reaction is stirred at room temperature for48 h. Di-tert-butyl dicarbonate (17.6 g, 0.080 mol) and triethylamine(16.8 mL, 0.120 mol) are added. Stirring is continued for 16 h. Thereaction mixture is filtered to remove triethylamine-HCl and the solventis removed by rotary evaporation under high vacuum to give a thick oil.The oil is dissolved in 150 mL CH₂Cl₂ and applied to a silica gel column(150 g, 40×250 mm). The column is eluted with 3% methanol in CH₂Cl₂ togive the crude product as a solid. The crude solid is dissolved in 120mL hot CH₂Cl₂ and cooled to −20° C. for 1 h. The resulting solid isfiltered and washed with 50 mL CH₂Cl₂. The combined filtrates areevaporated to dryness. CH₂Cl₂ (40 mL) is added to this residue and theresulting slurry is stirred for 0.5 h at room temperature. The slurry isfiltered and the solid washed with 25 mL CH₂Cl₂. The solids are combinedto give 5.57 g of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one. 300MHz ¹H NMR (DMSO) δ 7.42 (1 H, t, J =5.1 Hz), 6.38 (1 H, d, J=6.6 Hz),4.60 (1 H, d, J=4.2 Hz), 4.07 (1 H, m), 3.74 (1 H, m), 3.32 (1 H, m),3.03 (1 H, m), 1.8-1.5 (4 H, m), 1.39 (9 H, s).

g) Preparation of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-t-butyl-dimethylsilyloxy-2H-azepin-2-one

To a stirred solution of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one (25g, 102 mmol) in DMF (60 mL) is added tert-butyldimethylsilyl chloride(23.16 g, 153 mmol), and imidazole (10.45 g, 153 mmol). The reaction isstirred at room temperature for 18 h, diluted with 1 L of water andextracted with a 1:1 (2×200 mL) mixture of ethyl acetate and hexane. Allorganic layers are combined, washed with brine, dried with NaSO₄, andconcentrated under vacuum. The residue is purified by recrystallizationwith ethyl acetate/hexane to give 28.5 g (78%) of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-tert-butyldimethylsilyloxy-2H-azepin-2-oneas a white solid, melting point: 65-66° C.; ¹H NMR (CDCl₃) δ 5.86 (d,J=6 Hz, 1H), 5.58 (t, J=6Hz, 1H), 4.18 (m, 1H), 3.91 (s, 1H), 3.35(dd,J=6 Hz and 16 Hz, 1H), 3.07 (m, 1H), 1.80 (m, 4H), 1.40 (s, 9H), 0.83(s, 9H), 0.004 (s, 6H).

h) Preparation of[(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl]-carbamicacid tert-butyl ester

To a stirred solution of[(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-azepan-3-yl]-carbamicacid tert-butyl ester (4.0 g, 11.1 mmol) in THF (30 mL) at −78° C. isadded KN(Si(CH₃)₃)₂ (45.0 mL 1M THF, 45.0 mmol) slowly. The mixture isstirred at room temperature for 20 min, cooled to −78° C., and3-chloromethyl-pyridine hydrochloride (2.75 g, 16.7 mmol) is added inportions. The reaction is warmed to room temperature and stirred for 16h, H₂O (20 mL) is added and the mixture is partitioned with H₂O/ether,the organic layer is separated, dried with Na₂SO₄ and evaporated to givea white solid, 5.0 g (quantitative) of[(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl]-carbamicacid tert-butyl ester. MS (ESI) 899.3 (2M+H)⁺.

i) Preparation of(3S,6R)-3-amino-6-(tert-butyl-dimethyl-silanyloxy)-1-pyridin-3-ylmethyl-azepan-2-one

To a stirred solution of[(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl]-carbamicacid tert-butyl ester (5.0 g, 11.1 mmol) in CH₂Cl₂ (50 mL) at −78° C. isadded trimethylsilyl iodide (2.8 g, 14.0 mmol) neat. After 30 min thereaction solution is warmed to 0° C. and stirred for 15 min. Thereaction is quenched with a solution of CH₃OH (25 mL) and NH₄HCO₃ (10mL, saturated in H₂O), and partitioned with H₂O/CH₂Cl₂. The CH₂Cl₂fraction is dried over Na₂SO₄ and evaporated to a gum andchromatographed on silica (95% CH₂Cl₂/5% CH₃OH) to give 3.6 g (92.6%) of(3S,6R)-3-amino-6-(tert-butyl-dimethyl-silanyloxy)-1-pyridin-3-ylmethyl-azepan-2-oneas a white solid. MS (ESI) 350.2 (M+H)⁺.

j) Preparation of(R)—N-[(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl]-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamide

A solution of(3S,6R)-3-amino-6-(tert-butyl-dimethyl-silanyloxy)-1-pyridin-3-ylmethyl-azepan-2-one(1.84 g, 5.3 mmol),(4R,4aR)-4-((E)-3,3-Dimethyl-but-1-enyl)-7-methoxy-2,2-dimethyl-tetrahydro-furo[3,2-d][1,3]dioxin-6-one(1.0 g, 3.5 mmol) and diisopropylethylamine (1.37 g, 11.0 mmol) inisopropanol (10 mL) is refluxed for 16 h. The solution is evaporated andchromatographed on silica (95% CH₂Cl₂/5% CH₃OH) to give 1.27 g (57.0%)of(R)—N-[(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl]-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamideas a white solid. MS (ESI) 634.3 (M+H)⁺.

Preparation of(R)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-N-((3S,6R)-6-hydroxy-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl)-2-methoxy-acetamide

To a stirred solution of(R)—N-[(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl]-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamide(1.2 g, 1.9 mmol) at room temperature is added tetrabutylammoniumfluoride (5.68 mL, 1 M THF, 5.68 mmol). After 2 h, the solution isevaporated and chromatographed on silica (95% CH₂Cl₂/5% CH₃OH) to give0.74 g (75.2%) of(R)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-N-((3S,6R)-6-hydroxy-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl)-2-methoxy-acetamideas a white solid. ¹H NMR 300 MHz δ 8.52(m, 2H), 7.69 (m, 1H), 7.29 (m,1H), 5.77 (d, 1H), 5.54(dd, 1H), 4.69 (m, 2H), 4.29 (m, 2H), 4.10 (m,2H), 3.92 (d, 1H), 3.54 (m, 2H), 3.50 (s, 3H), 3.33 (m,2H), 2.15 (m,1H), 2.00 (m, 1H), 1.90 (m, 1H), 1.67 (m, 3H), 1.46 (m, 4H), 1.04 (s,9H), 1.00 (t, 2H); MS (ESI) 520.2 (M+H)⁺.

l) Preparation of tetradecanoic acid(3R,6S)-6-{(R)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetylamino}-7-oxo-1-pyridin-3-ylmethyl-azepan-3-ylester

To a stirred solution of tetradecanoic acid (0.39 g 1.7 mmol) and 4dimethylaminopyridine (0.21 g, 1.7 mmol) in CH₂Cl₂ (15 mL) is added1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.34 g,1.7 mmol) at room temperature. After 30 m in(R)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-N-((3S,6R)-6-hydroxy-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl)-2-methoxy-acetamide(0.74 g, 1.4 mmol) is added and stirred for 16 h. The reaction isconcentrated and chromatographed on silica (98% CH₂Cl₂/2% CH₃OH) to give0.3 g (28.8%) of tetradecanoic acid(3R,6S)-6-{(R)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetylamino}-7-oxo-1-pyridin-3-ylmethyl-azepan-3-ylester as a white solid. ¹H NMR 300 MHz δ 8.54(s, 2H), 7.88 (d, 1 H),7.63 (d, 1 H), 7.29 (m, 1H), 5.77 (d, 1H), 5.54(dd, 1H), 5.06 (d, 1H),4.75 (m, 1H), 4.50 (m, 1H), 4.29 (m, 2H), 4.08 (d, 1H), 3.90 (d, 1H),3.52 (s, 3H), 3.50 (m, 1H), 3.25 (d, 1H), 2.27 (t, 2H), 2.15 (m, 2H),2.00 (m, 1H), 1.60 (m, 3H), 1.46 (d, 2H), 1.25 (m, 24H), 1.04 (s, 9H),0.88 (t, 3H); MS (ESI) 730.3 (M+H)⁺.

m) Preparation of title compound tetradecanoic acid(3R,6S)-7-oxo-1-pyridin-3-ylmethyl-6-((2R,3R,4S,5R)-(E)-3,4,5trihydroxy-2-methoxy-8,8-dimethyl-non-6-enoylamino)-azepan-3-ylester

To a solution of TFA/THF/H₂O (3/3/2) (30 mL) at 0° C. is addedtetradecanoic acid(3R,6S)-6-{(R)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetylamino}-7-oxo-1-pyridin-3-ylmethyl-azepan-3-ylester (0.3 g, 0.42 mmol). After 30 min the reaction is evaporated underhigh vacuum, toluene is added (20 mL) and evaporated under high vacuumto remove remaining TFA. The residue is dissolved in CH₂Cl₂ at 0° C. andneutralized by adding NH₄OH dropwise. The solution is concentrated andchromatographed on silica (98% CH₂Cl₂/2% CH₃OH) to give 0.2 g (70.7%) oftetradecanoic acid(3R,6S)-7-oxo-1-pyridin-3-ylmethyl-6-((2R,3R,4S,5R)-(E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enoylamino)-azepan-3-ylester as a with solid. ¹H NMR 300 MHz δ 8.62 (s, 2H), 8.17 (d, 1H), 7.67(d, 1H), 7.33 (m, 1H), 5.83 (d, 1H), 5.42(dd, 1H), 4.69 (m, 1H), 4.54(m, 1H), 4.33 (d, 1H), 4.32 (t, 1H), 3.83 (dd, 2H), 3.67 (d, 1H), 3.25(s, 3H), 3.17 (m, 1H), 2.94 (d, 1H), 2.29 (t, 2H), 2.13 (m, 2H), 2.00(m, 1H), 1.60 (m, 3H), 1.29 (m, 24H), 1.04 (s, 9H), 0.89 (t, 3H); MS(ESI) 690.3 (MA+H)⁺.

Example 2(E)-(2R,3R,4S,5R)-3,4,5-Trihydroxy-2-methoxy-8,8-dimethyl-non-6-enoicacid [(3S,6R)-6-(6-amino-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-amide

a) Preparation of[(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-1-methyl-2-oxo-azepan-3-yl]-carbamicacid tert-butyl ester

Following the procedure of Example 1(f)-1(h), except CH₃-I issubstituted for 2-chloromethyl-pyridine and one equivalent ofKN(Si(CH₃)₃)₂ is used in step 1(h) to give the product as an oil. ¹H NMR(CDCl₃) δ 0.05 (s, 3H), 0.07 (s, 3H), 0.87 (s, 9H), 1.44 (s, 9H), 1.8(m, 4H), 3.06 (s, 3H), 3.2 (dd, 1H), 3.7 (d, 1H), 4.0 (m, 1H). 4.28 (dd,1H), 6.0 (d, 1H).

b) Preparation of((3S,6R)-6-hydroxy-1-methyl-2-oxo-azepan-3-yl)-carbamic acid tert-butylester

To a solution of[(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-1-methyl-2-oxo-azepan-3-yl]-carbamicacid tert-butyl ester (0.85 g, 2.27 mmol) in THF (40 mL) is addedtetrabutylammonium fluoride (3 mL 1M THF, 3 mmol) at room temperature.The reaction solution is stirred for 4 h, then H₂O (40 mL) is added andthe solution concentrated under vacuum to ½ its volume and extracted 3×with CH₂Cl₂ (40 mL). The combined CH₂Cl₂ extracts are adsorbed on silicaand chromatographed (5% CH₃OH/CH₂Cl₂) to give 0.568 g (72%) of((3S,6R)-6-hydroxy-1-methyl-2-oxo-azepan-3-yl)-carbamic acid tert-butylester as a white solid. ¹H NMR (CDCl₃) δ 1.44 (s, 9H), 1.7-2.05 (m, 4H),3.1 (s, 3H), 3.37 (dd, 1H), 3.73 (d, 1H), 4.07 (m, 1H), 4.31 (m, 1H),6.0 (d, 1H).

Preparation of[(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-carbamic acidtert-butyl ester

To a stirred solution of((3S,6R)-6-hydroxy-1-methyl-2-oxo-azepan-3-yl)-carbamic acid tert-butylester (0.70 g, 2.6 mmol) in THF (5 mL) cooled to −78° C. is addedNaN(Si(CH₃)₃)₂ (2.8 mL 1M THF, 2.8 mmol). After 10 mintrifluoro-methanesulfonic acid 6-azido-hexyl ester (0.76 g, 3.1 mmol) isadded neat and stirred for 10 min at −78° C. then warmed and stirred atroom temperature for 1 h. NaHCO₃ (5 mL 1M H₂O) is added and the solutionis partitioned with H₂O/EtOAc, the EtOAc extract is dried with Na₂SO₄and evaporated to an oil. The oil is adsorbed on silica andchromatographed (20% EtOAc/CH₂Cl₂) to give 0.32 g (32%) of[(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-carbamic acidtert-butyl ester as an oil. ¹H NMR (CDCl₃) δ 1.34 (s, 9H), 1.24-2.1 (m,12H), 2.95 (s, 3H), 3.1-3.35 (m, 6H), 3.44 (m, 1H), 3.55 (d, 1H), 4.2(m, 1H).

Preparation of(3S,6R)-3-amino-6-(6-azido-hexyloxy)-1-methyl-azepan-2-one

To a stirred solution of[(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-carbamic acidtert-butyl ester (0.32 g, 0.83 mmol) in CH₂Cl₂ (4 mL) is added TFA (1mL) at room temperature. After 1 h, the reaction is evaporated undervacuum, toluene (20 mL) is added and evaporated under vacuum to removeremaining TFA. The residue is dissolved in CH₂Cl₂ (20 mL) saturated withNH₃ adsorbed on silica and chromatographed (50% EtOAc/CH₂Cl₂/NH₃ then10% CH₃OH/CH₂Cl₂/NH₃) to give 0.207 g (88%) of(3S,6R)-3-amino-6-(6-azido-hexyloxy)-1-methyl-azepan-2-one as an oil. MS(ESI) 284.2 (M+H)⁺.

Preparation of(R)—N-[(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamide

To a solution of(3S,6R)-3-amino-6-(6-azido-hexyloxy)-1-methyl-azepan-2-one (0.207 g,0.73 mmol) in isopropanol (1 mL) is added(4R,4aR)-4-((E)-3,3-dimethyl-but-1-enyl)-7-methoxy-2,2-dimethyl-tetrahydro-furo[3,2-d][1,3]dioxin-6-one(0.3 g, 1 mmol) and heated to reflux for 18 h. The solution isevaporated under vacuum adsorbed on silica and chromatographed (CH₂Cl₂to EtOAc gradient) to give 0.245 g (59%) of(R)-N-[(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamideas a solid. (ESI) 568.1 (M+H)⁺.

f) Preparation of(E)-(2R,3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enoicacid [(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-amide

Following the procedure of Example 1 m) except(R)—N-[(3S,6R)-6-(6-azido-hyxyloxy)-1-methyl-2-oxo-azepan-3-yl]-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamideis substituted for tetradecanoic acid (3R,6S)-6-{(R)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetylamino}-7-oxo-1-pyridin-3-ylmethyl-azepan-3-ylester. MS (ESI) 528.0 (M+H)⁺.

g) Preparation of title compound(E)-(2R,3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enoicacid [(3S,6R)-6-(6-amino-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-amide

To a stirred solution of(E)-(2R,3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enoicacid [(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-amide(0.13 g, 0.25 mmol) in THF (2 mL) is added H₂O and triphenylphosphine(0.120 g, 0.5 mmol). After 8 h the reaction solution is evaporated undervacuum to give a semisolid residue that is dissolved in CH₂Cl₂ (10 mL),adsorbed on silica and chromatographed (CH₂Cl₂/NH₃ to 25%CH₃OH/CH₂Cl₂/NH₃ gradient) to give 0.106 g (85%) of(E)-(2R,3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enoicacid [(3S,6R)-6-(6-amino-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-amide asa white solid. MS (ESI) 502.1 (M+H)⁺

Example 3(E)-(2R,3R,4S,5R)-3,4,5-Trihydroxy-2-methoxy-8,8-dimethyl-non-6-enoicacid ((3S,6S)-6-azido-2-oxo-azepan-3-yl)-amide

Preparation of ((3S,6S)-6-azido-2-oxo-azepan-3-yl)-carbamic acidtert-butyl ester

To a stirred solution of ((3S,6R)-6-hydroxy-2-oxo-azepan-3-yl)-carbamicacid tert-butyl ester (3 g, 12.3 mmol example 1 f) andtriphenylphosphine (3.75 g, 14.1 mmol) in THF (200 mL) at 0° C. is addeddiethyl azodicarboxylate (2.2 mL, 13.5 mmol) at a rate to maintain atemperature <5° C. followed immediately by addition ofdiphenylphosphoryl azide (2.9 mL, 13.5 mmol). The reaction is stirredfor 60 h at room temperature in the dark, the solvent is removed undervacuum and the residue chromatographed on silica (hexane to ethergradient) to give 2.33 g (70%) of((3S,6S)-6-azido-2-oxo-azepan-3-yl)-carbamic acid tert-butyl ester as asolid. MS (ESI) 270 (M+H)⁺

Preparation of (3S,6S)-3-amino-6-azido-azepan-2-one

Following the procedure of example 2 d)((3S,6S)-6-azido-2-oxo-azepan-3-yl)-carbamic acid tert-butyl ester issubstituted for[(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-carbamic acidtert-butyl ester to give (3S,6S)-3-amino-6-azido-azepan-2-one. MS (ESI)170 (M+H)⁺

Preparation of(R)—N-((3S,6S)-6-azido-2-oxo-azepan-3-yl)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamide

Following the procedure of example 2 e)(3S,6S)-3-amino-6-azido-azepan-2-one is substituted for(3S,6R)-3-amino-6-(6-azido-hexyloxy)-1-methyl-azepan-2-one to give(R)—N-((3S,6S)-6-azido-2-oxo-azepan-3-yl)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamide.MS (ESI) 454.2 (M+H)⁺

d) Preparation of title compound(E)-(2R,3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enoicacid ((3S,6S)-6-azido-2-oxo-azepan-3-yl)-amide

Following the procedure of example 1 m)(R)—N-((3S,6S)-6-azido-2-oxo-azepan-3-yl)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamideis substituted for tetradecanoic acid(3R,6S)-6-{(R)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetylamino}-7-oxo-1-pyridin-3-ylmethyl-azepan-3-ylester to give the title compound. MS (ESI) 414.2 (M+H)⁺

Example 4[(S)-2-Oxo-3-((2R,3R,4S,5R)-(E)-3,4,5-trihydroxy-2-methoxy-8-methyl-non-6-enoylamino)-azepan-1-yl]-aceticacid benzyl ester

Preparation of(4R,4aR)-7-methoxy-2,2-dimethyl-4-((E)-3-methyl-but-1-enyl)-tetrahydro-furo[3,2-d][1,3]dioxin-6-one

Following the procedure of example 1 a)-e) except1,1-diiodo-2-methyl-propane is substituted for1,1-diiodo-2,2-dimethyl-propane to give(4R,4aR)-7-methoxy-2,2-dimethyl-4-((E)-3-methyl-but-1-enyl)-tetrahydro-furo[3,2-d][1,3]dioxin-6-oneas a white solid. ¹HNMR (CDCl₃) δ 5.85 (dd, J=15.6, 6.22 Hz, 1H), 5.64(ddd, J=15.6, 7.5, 1.27 Hz, 1H), 4.74 (dd, J=3.79, 2.09 Hz, 1H), 4.48(dd, J=7.49, 1.78 Hz, 1H), 4.12 (d, J=3.86 Hx, 1H), 4.02 (t, J=2.02 Hz,1H), 3.68 (s, 3H), 2.36 (m, 1H), 1.56 (s, 3H), 1.51 (s, 3H), 1.04 (d,J=1.9 Hz, 3H), 1.03 (d, J=1.9 Hz, 3H); ¹³C NMR (CDCl₃) δ 172.8, 143.2,122.0, 98.7, 79.0, 71.7, 70.0, 67.6, 59.2, 30.7, 29.2, 21.9, 21.8, 19.2.HRMS: calculated for (M+Na)⁺(C₁₄H₂₂O₅Na) 293.1365, found 293.1355.

Preparation of ((S)-3-amino-2-oxo-azepan-1-yl)-acetic acid benzyl ester

Following the procedure of example 1 h) except((S)-2-oxo-azepan-3-yl)-carbamic acid tert-butyl ester is substitutedfor[(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-azepan-3-yl]-carbamicacid tert-butyl ester and bromo-acetic acid benzyl ester is substitutedfor 2-chloromethyl-pyridine and one equivalent of KN(Si(CH₃)₃)₂ base togive ((S)-3-tert-butoxycarbonylamino-2-oxo-azepan-1-yl)-acetic acidbenzyl ester. Removal of the Boc group by procedure 2 d) gives((S)-3-amino-2-oxo-azepan-1-yl)-acetic acid benzyl ester.

c) Preparation of title compound[(S)-2-oxo-3-((2R,3R,4S,5R)-(E)-3,4,5-trihydroxy-2-methoxy-8-methyl-non-6-enoylamino)-azepan-1-yl]-aceticacid benzyl ester

The product of 4 b) is processed as in example 2 e)-f) to give the titlecompound as a white solid.

Examples 5-59

The following compounds are prepared by similar methods utilizinganalogous starting materials:

Example 5MS ESI 569.3 (M + H)⁺

Example 6MS ESI 717.2 (M + H)⁺

Example 7MS ESI 641.5 (M + H)⁺

Example 8MS ESI 464.4 (M + H)⁺

Example 9MS ESI 542.3 (M + Na)⁺

Example 10MS ESI 463.3 (M + H)⁺

Example 11MS ESI 542.3 (M + H)⁺

Example 12MS ESI 430.2 (M + H)⁺

Example 13MS ESI 472.3 (M + H)⁺

Example 14MS ESI 591.2 (M + H)⁺

Example 15MS ESI 431.2 (M + H)⁺

Example 16MS ESI 656.4 (M + H)⁺

Example 17MS ESI 446.2 (M + H)⁺

Example 18MS ESI 546.3 (M + H)⁺

Example 19MS ESI 637.1 (M + H)⁺

Example 20MS ESI 689.4 (M + H)⁺

Example 21MS ESI 479.2 (M + H)⁺

Example 22MS ESI 479.2 (M + H)⁺

Example 23MS ESI 472.2 (M + H)⁺

Example 24MS ESI 689.2 (M + H)⁺

Example 25MS ESI 657.3 (M + H)⁺

Example 26MS ESI 514.1 (M + H)⁺

Example 27MS ESI 488.1 (M + H)⁺

Example 28MS ESI 430.2 (M + H)⁺

Example 29MS ESI 598.2 (M + H)⁺

Example 30MS ESI 642.3 (M + H)⁺

Example 31MS ESI 528.0 (M + H)⁺

Example 32MS ESI 521.2 (M + H)⁺

Example 33MS ESI 1197.4 (2M + H)⁺

Example 34MS ESI 519.0 (M + H)⁺

Example 35MS ESI 393.0 (M + H)⁺

Example 36MS ESI 398.5 (M + H)⁺

Example 37

Example 38MS ESI 375.1 (M + H)⁺

Example 39MS ESI 401.21 (M + H)⁺

Example 40MS ESI 417.1 (M + H)⁺

Example 41MS ESI 359.3 (M + H)⁺

Example 42MS ESI 569.5 (M + H)⁺

Example 43MS ESI 443.4 (M + H)⁺

Example 44MS ESI 459.4 (M + H)⁺

Example 45MS ESI 409.3 (M + H)⁺

Example 46MS ESI 387.3 (M + H)⁺

Example 47MS ESI 387.3 (M + H)⁺

Example 48MS ESI 549.3 (M + H)⁺

Example 49MS ESI 375.3 (M + H)⁺

Example 50MS ESI (M + H)⁺

Example 51MS ESI 387.3 (M + H)⁺

Example 52MS ESI 371.2 (M + H)⁺

Example 53MS ESI 423.2 (M + H)⁺

Example 54MS ESI 585.4 (M + H)⁺

Example 55MS ESI 435.0 (M + H)⁺

Example 56MS ESI 387.2 (M + H)⁺

Example 57MS ESI 387.3 (M + H)⁺

Example 58MS ESI 387.2 (M + H)⁺

Example 59

The anti-tumor activity of the compounds of formula I may bedemonstrated employing the Anchorage Dependent Growth Monolayer Assay(ADGMA) which measures the growth inhibitory effects of test compoundson proliferation of adherent cell monolayers. This assay was adaptedfrom the 60 cell line assay used by the National Cancer Institute (NCl)with the following modifications: 1) cell lines representative for theimportant tumor types, for example, MDA-MB-435 breast and A549 non-smallcell lung, are utilized; and 2) a tetrazolium derivative, viz., MTS, isutilized to determine cell density.

The ADGMA compares the number of viable cells following a 3-day exposureto a test compound relative to a number of cells present at the time thetest compound is added. Cell viability is measured using a tetrazoliumderivative, viz.,3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt (MTS) that is metabolically reduced in the presence of anelectron coupling agent (PMS; phenazine methosulfate) by viable cells toa water-soluble formazan derivative. The absorbance at 490 nm (A₄₉₀) ofthe formazan derivative is proportional to the number of viable cells.The IC₅₀ for a test compound is the concentration of compound requiredto reduce the final cell number to 50% of the final control cell number.

The MDA-MB-435 breast carcinoma line is obtained from the American TypeCulture Collection (ATCC) and used between passages 4-20 followingthawing. MDA-MB-435 breast carcinoma is maintained and plated in DME/F12medium containing 10% fetal bovine serum, 15 mM HEPES (pH=7.4),penicillin 100 units/mL, and streptomycin 100 micrograms/mL.

The A549 non-small cell lung lines are obtained from the American TypeCulture Collection (ATCC) and used between passages 4-20 followingthawing. A549 cells are maintained in RPMI 1640 containing 5% FBS, 5mg/mL insulin, 5 mg/mL transferring, 5 mg/mL selenous acid, 1 nMβ-estradiol, 1 nM testosterone, 100 units/mL penicillin and 100 ug/mLstreptomycin.

Cell lines are trypsinized and counted using a Coulter counter todetermine plating densities. Cells are then plated in their respectivemaintenance media (100 μL/well) in 96 well plates at the followingdensities: MDA-MB-435, 3,000 cells/well; A549, 700 cells/well. Thenumber of cells plates as determined in preliminary experiments, resultsin cell densities of 75-90% of confluency by 4 days after plating.Initial cell densities, assayed one day after plating, are roughly0.15-0.20 absorbance units greater than the media blank. Ninety-six wellplates are seeded on day 0 and the test compounds are added on day 1. Acontrol plate is created for each cell line that receives media only inrow A and cells in row B. One day following plating, test compounds areadded (in a final volume of 100 μL) to the test plates. Control platesreceive 10 μL MTS mixture (prepared fresh on day of addition to cellplates at a ratio of 10 μL of a 0.92 mg/mL solution of PMS to a 190 μLof a 2 mg/mL solution of MTS) and 100 μL media. A₄₉₀ of control platesis read 4 h after MTS addition to determine initial cell density valuesfor each cell line. Three days after addition of the test compound, 10μL/well of MTS mixture is added to the test plates and A₄₉₀ is read 4 hlater. A₄₉₀ values for wells containing cells are corrected for mediaabsorbance, then normalized to initial density readings to determinepercent net growth. IC₅₀ values are determined from graphs of percentnet growth as a function of compound concentration. Percent net growthis calculated as

(Cell+Drug A₄₉₀−Initial A₄₉₀/Cell+Drug Vehicle A₄₉₀−Initial A₄₉₀).

Each of the compounds of Examples 1-59 shows an 1C₅₀ value in the rangefrom 0.001 μM to 100 μM in the ADGMA with at least one carcinoma cellline.

1. Use of a compound of formula I for the treatment of cancer, whereinformula I comprises:

or a salt thereof, wherein n is 0, 1 or 2; R1 is H, X₁—(C₁₋₆) alkyl-,(C₁₋₁₂)alkylC(O)—, X₂—(C₂₋₄) alkenylene-, X₂-(C₂₋₄) alkynylene-,X₁—(C₃₋₉)cycloalkyl-, X₂-(C₃₋₉)cycloalkene-, X₁-aryl-,X₁—(C₃₋₇)cycloalkane-(C₁₋₆)alkylene-,X₂—(C₃₋₇)cycloalkene-(C₁₋₆)alkylene-, or X₁-aryl-(C₁₋₆)alkylene-; X₁ isH, (C₁₋₁₄)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₁₄)alkyl substituted by(C₃₋₇)cycloalkyl, —OR_(a), —SR_(a), —NO₂, halo or (C₁₋₆)alkylC(O)—;aryl, aryl-(C₁₋₁₂)alkyl-, —OR_(a), —SR_(a), —NO₂, halo,(C₁₋₁₂)alkyl-C(O)—, mono- or di-(C₁₋₄)alkylamino, amino(C₁₋₁₆)alkyl-, ormono- or di-(C₁₋₄)alkylamino(C₁₋₁₆)alkyl; X₂ is H, (C₁₋₁₄)alkyl,(C₃₋₇)cycloalkyl, (C₁₋₁₄)alkyl substituted by (C₃₋₇)cycloalkyl,—OR_(a)—SR_(a), —NO₂, halo or (C₁₋₆)alkyl-C(O)—; aryl,aryl-(C₁₋₁₂)alkyl-, amino(C₁₋₁₆)alkyl- or mono- ordi-(C₁₋₁₄)alkylamino(C₁₋₁₆)alkyl; R_(a) is H, (C₁₋₁₈)alkyl, aryl, or(C₁₋₁₈)alkyl substituted by (C₃₋₇)cycloalkyl, aryl, —OH, —O—(C₁₋₆)alkylor halo; R₂, R₃, R₄ and R₅ are independently hydrogen or (C₁₋₁₈)alkyl,R₅ is also phenyl or (C_((C) ₁₋₁₆)alkyl which is substituted by phenyl,wherein there is no more than a total of 18 carbon atoms in the combinedR₂, R₃, R₄ and R₅ alkyl substituents, or R₂ and R₄ together or R₃ and R₅together form an acetal group; R6 is hydrogen or (C₁₋₆) alkyl; R7 is H,(C₁₋₁₈)alkyl, phenyl, pyridyl, (C₁₋₁₈)alkyl substituted by(C₃₋₇)cycloalkyl, —OR_(x), N₃, halo, —N(R_(x))₂, R_(x), —O—(C₁₋₆)alkyl,—OC(O)—(C₁₋₁₆)alkyl or pyridyl; —Y—Rb or a substituted of formula IIa orIIIa

wherein R9 is from 0 to 3 substituents selected from (C₁₋₆)alkyl,—OR_(a), —SR_(a), —NO₂, halo, —N₃, (C₁₋₁₂)alkylC(O)-, mono- ordi-(C₁₋₄)alkylamino, amino(C₁₋₁₆)alkyl-, mono- ordi-(C₁₋₄)alkylamino(C₁₋₁₆)alkyl, (CH₂)₀₋₂—C₅₋₇cycloalkyl,(CH₂)₀₋₂-heterocyclic, (CH₂)₀₋₂—C₅₋₇aryl, or (CH₂)₀₋₂-heteroaryl; Y is alinking group selected from —(C₁₋₁₀)alkyl-,—(C₀₋₁₀)alkylene-CO-N(R_(x))-(Co-₁₀)alkylene-,—(C₀₋₁₀)alkylene-N(R_(x))—CO—(C₀₋₁₀)alkylene-,—(C₀₋₁₀)alkylene-CO—O—(C₀₋₁₀)alkylene-,—(C₁₋₁₀)alkylene-O—C(O)—(C₁₋₁₀)alkylene-,—(C₀₋₁₀)alkylene-CO—(C₀₋₁₀)alkylene-,—(C₀₋₁₀)alkylene-(R_(x))N—CO—O—(C₀₋₁₀)alkylene-,—(C₀₋₁₀)alkylene-O—CO—(R_(x))N—(C₀₋₁₀)alkylene- or—(C₀₋₁₈)alkylene-arylene-(C₀₋₁₈)alkylene-; R_(x) is H, (C₁₋₄)alkyl orphenyl; R_(b) is (C₁₋₁₆)alkyl or (C₁₋₁₆)alkyl which is substituted by(C₃₋₇)cycloalkyl, —OR_(x), N₃, halo, —N(R_(x))₂, —O—(C₁₋₆)alkyl,—OC(O)—(C₁₋₁₆)alkyl or pyridyl; R8 is H, halo, —N₃, (C₁₋₁₆)alkyl,-Z-(C₁₋₁₆)alkyl, (C₁₋₁₆)alkyl substituted by (C_((C) ₃₋₇)cycloalkyl,—N₃, —N(R_(x))₂, -Z-het, —OR_(a) or —SR_(a), -Z-(C₁₋₁₆)alkyl substitutedby (C₃₋₇)cycloalkyl, —N₃, —N(R_(x))₂, -Z-het, —OR_(a) or —SR_(a),—O(C₁₋₁₆)alkylene-N₃, —O(C₁₋₁₆)alkylene-N(R_(x))₂,—(C₀₋₆)alkylene-OC(O)—(C₁₋₁₆)alkyl, —(C₀₋₆)alkylene-(O)C—O—(C₁₋₁₆)alkyl,—(C₀₋₆)alkylene-OC(O)—(C₃₋₇)cycloalkyl,—(C₀₋₆)alkylene-(O)C—O—(C₃₋₇)cycloalkyl, pyridyl, —OC(O)O(C₁₋₁₂)alkyl,—O—CO—X—R_(z), or —O—CO—(CH₂)_(m)—O—(CH₂)_(m)—X—R_(z) wherein X is adirect bond, (C₁₋₁₂)alkylene, (C₁₋₁₂)alkenylene or (C₁₋₁₂)alkynylene andR_(z) is H, (C₃₋₉)cycloalkyl, phenyl, phenyl substituted by one or moreof chloro, methoxy, (C₁₋₁₈)alkyl or (C₁₋₁₈)alkoxy, pyrrolyl, furanyl,thiofuranyl, indolyl, benzofuranyl, benzothiofuranyl or pyridyl and eachm is independently a number from 0 to 13,-Z-het, —OR_(a), —SR_(a), mono-or di-(C₁₋₄)alkylamino, amino(C₁₋₁₆)alkyl-, mono- ordi-(C₁₋₄)alkylamino(C₁₋₁₆)alkyl, -Z-Si((C₁₋₆)alkyl)₃ or a substituentselected from the following two formulae:

Z is a direct bond, —(C₁₋₁₂)alkylene-, —(C₁₋₁₂)alkylene-O—,—O—(C₁₋₁₂)alkylene-, —(C₁₋₁₂)alkylene-N(R_(x))—, —N(R_(x))—,—N(R_(x))—(C₁₋₁₂)alkylene-, —N(R_(x))—C(O)—,—N(R_(x))—C(O)—(C₁₋₁₂)alkylene-, —(C₁₋₁₂)alkylene-N(R_(x))—C(O)—,—(C₁₋₈)alkylene-N(R_(x))—C(O)—(C₁₋₈)alkylene-,—(C₁₋₁₂)alkylene-CO—N(R_(x))—, —CO—N(R_(x))—(C₁₋₁₂)alkylene-,—(C₁₋₈)alkylene-CO—N(R_(x))—(C₁₋₈)alkylene-, —CO—N(R_(x))—,—(C₁₋₁₂)alkylene-CO—O—, —(C₁₋₁₂)alkylene-O—C(O)—,—OC(O)—(C₁₋₁₂)alkylene-, —C(O)—O—(C₁₋₁₂)alkylene-, —(C₁₋₁₂)alkylene-CO—,—(C₁₋₈)alkylene-CO—(C₁₋₈)alkylene-, —CO—(C₁₋₁₂)alkylene-, —C(O)—,—N(R_(x))—C(O)—O—, —N(R_(x))—C(O)—O—(C₁₋₁₂)alkylene-,—(C₁₋₁₂)alkylene-N(R_(x))—C(O)—O—,—(C₁₋₈)alkylene-N(R_(x))—C(O)—O—(C₁₋₈)alkylene-,—(C₁₋₁₂)alkylene-O—CO—N(R_(x))—, —O—CO—N(R_(x))—(C₁₋₁₂)alkylene-,—(C₁₋₈)alkylene-O—CO—N(R_(x))—(C₁₋₈)alkylene-, —O—CO—N(R_(x))—,—O—CO—O—, —(C₁₋₁₂)alkylene-O—CO—O—, —O—CO—O—(C₁₋₁₂)alkylene- or—(C₁₋₈)alkylene-O—C(O)—O—(C₁₋₈)alkylene-; Z₁ is a direct bond,—(C₁₋₁₂)alkylene-, —O—(C₁₋₁₂)alkylene-, —N(R_(x))—(C₁₋₁₂)alkylene-,—N(R_(x))—C(O)—(C₁₋₁₂)alkylene-,—(C₁₋₈)alkylene-N(R_(x))—C(O)—(C₁₋₈)alkylene-,—CO—N(R_(x))—(C₁₋₁₂)alkylene-,—(C₁₋₈)alkylene-CO—N(R_(x))—(C₁₋₈)alkylene-, —OC(O)—(C₁₋₁₂)alkylene-,—C(O)—O—(C₁₋₁₂)alkylene-, —(C₁₋₈)alkylene-CO—(C₁₋₈))alkylene-,—CO—(C₁₋₁₂)alkylene-, —C(O)—, —N(R_(x))—C(O)—O—(C₁₋₁₂)alkylene-,—(C₁₋₈)alkylene-N(R_(x))—C(O)—O—(C₁₋₈)alkylene-,—O—CO—N(Rx)—(C₁₋₁₂)alkylene-,—(C₁₋₈)alkylene-O—CO—N(R_(x))—(C₁₋₈)alkylene-, —O—CO—O—(C₁₋₁₂)alkylene-or —(C₁₋₈)alkylene-O—C(O)—O—(C₁₋₈)alkylene-; R10 is from 0 to 3substituents selected from hydroxy, halo, -(C₁ ₁₇)alkyl,—O—(C₁₋₁₇)alkyl, —(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —(CH₂)₀₋₁₀-aryl or—(CH₂)₀₋₁₀-het; het is a heterocyclic or heteroaromatic ring; p is ₁₋₁₈;with the proviso that when n is 2 and R₁ is (C₁₋₆)alkyl-CH═CH— or(C₃₋₆)cycloalkyl-CH═CH—then R₇ is not H or (C₁₋₈)alkyl or R₈ is not—O—CO—X-R_(Z) or —O—CO—(CH₂)_(m—O—(CH) ₂)_(m)—X-R_(Z) where X is adirect bond, (C₁₋₁₂)alkylene, (C₁₋₁₂)alkenylene or (C₁₋₁₂)alkynylene andR_(z) is H, (C₃₋₉)cycloalkyl, phenyl, phenyl substituted by one or moreof chloro, methoxy, (C₁₋₁₈)alkyl or (C₁₋₁₈)alkoxy, pyrrolyl, furanyl,thiofuranyl, indolyl, benzofuranyl, benzothiofuranyl or pyridyl and eachm is independently a number from 0 to 13, and with the further provisothat R₈ is not —OH when n is 2, R₇ is H or methyl and R₁ is3-methylbut-1-enylene.
 2. Use of the compound of claim 1, or a saltthereof, wherein: n is 2; R1 is X₁—(C₁₋₆) alkyl-, X₂—(C₂₋₄) alkenylene-,X₁—(C₃₋₇)cycloalkyl-, or X₁—(C₃₋₃)alkylene-; X₁ is H, (C₁₋₁₂)alkyl,(C₃₋₇)cycloalkyl, —(C₁₋₁₂)alkyl substituted by (C₃₋₇)cycloalkyl,—OR_(a); —SR_(a), —NO₂, halo or (C₁₋₁₂)alkylC(O)—; aryl,aryl-(C₁₋₁₂)alkyl- or —OR_(a); X₂ is H, (C₁₋₁₂)alkyl, (C₃₋₇)cycloalkyl,—(C₁₋₁₂)alkyl substituted by (C₃₋₇)cycloalkyl, —OR_(a), —SR_(a), —NO₂,halo or (C₁₋₁₂)alkylC(O)-, aryl, aryl-(C₁₋₁₂)alkyl-; R_(a) is H,(C₁₋₁₈)alkyl, aryl-, or (C₁₋₁₈)alkyl substituted by (C₃₋₇)cycloalkyl oraryl; R₂, R₃, R₄ and R₅ are independently hydrogen or (C₁₋₄)alkyl,wherein there is no more than a total of 8 carbon atoms, especially nomore than 4 carbon atoms, in the combined R₂, R₃, R₄ and R₅ alkylsubstituents; R6 is hydrogen or (C₁₋₆) alkyl; R7 is H, (C₁₋₈)alkyl,R_(x), (C₁₋₁₈)alkyl substituted by (C₃₋₇)cycloalkyl, —OR_(x), N₃, halo,—N(R_(x))₂, —O—(C₁₋₆)alkyl, —OC(O)—(C₁₋₁₆)alkyl or pyridyl; or asubstituent of formula IIa or IIIa

R9 is from 0 to 3 substituents selected from (C₁₋₆)alkyl, —OR_(a),—SR_(a), —NO₂, halo, or —N₃; Y is a linking group selected from—C(O)N(R_(x))—, —CO—O—, —(C₁₋₁₂)alkylene-CO—O—, —CO—O—(C₁₋₁₂)alkylene-,—(C₁₋₁₀)alkylene-CO—O—(C₁₋₁₀)alkylene-,—(C₁₋₁₀)alkylene-O—C(O)—(C₁₋₁₀)alkylene-, —CO—, —(C₁₋₁₂)alkylene-CO—,—CO—(C₁₋₁₂)alkylene-, —(C₁₋₁₀)alkylene-CO—(C₁₋₁₀)alkylene-,—(C₁₋₁₂)alkylene-(R_(x))N—CO—,—(C₁₋₁₀)alkylene-(R_(x))N—CO—O—(C₁₋₁₀)alkylene-, or—(C₀₋₁₂)alkylene-arylene-(C₀₋₁₂)alkylene-; R_(x) is H, (C₁₋₄)alkyl orphenyl; R8 is —N₃, (C₁₋₁₆)alkyl, -Z-(C₁₋₁₆)alkyl, (C₁₋₁₆)alkylsubstituted by (C₃₋₇)cycloalkyl, —N₃, or —N(R_(x))₂; -Z-(C₁₋₁₆)alkylsubstituted in the alkyl portion by (C₃₋₇)cycloalkyl, —N₃, or—N(R_(x))₂, —(C₀₋₆)alkylene-(O)C—O—(C₁₋₁₆)alkyl, or a substituentselected from the following two formulae:

Z is a direct bond, —(C₁₋₁₂)alkylene-, —N(R_(x))—C(O)—,—N(R_(x))—C(O)—(C₁₋₁₂)alkylene-, —(C₁₋₁₂)alkylene-N(R_(x))—C(O)—,—(C₁₋₈)alkylene-N(R_(x))—C(O)—(C₁₋₈)alkylene-,—(C₁₋₁₂)alkylene-CO—N(R_(x))—, —CO—N(R_(x))—(C₁₋₁₂)alkylene-,—(C₁₋₈)alkylene-CO—N(R_(x))—(C₁₋₈)alkylene-, —CO—N(R_(x))—,—C(O)—O—(C₁₋₁₂)alkylene-, —CO—(C₁₋₁₂)alkylene-, —C(O)—,—N(R_(x))—C(O)—O—, —N(R_(x))—C(O)—O—(C₁₋₁₂)alkylene-,—(C₁₋₁₂)alkylene-N(R_(x))—C(O)—O—,—(C₁₋₈)alkylene-N(R_(x))—C(O)—O——(C₁₋₈)alkylene-,—(C₁₋₁₂)alkylene-O—CO—N(R_(x))—, —O—CO—N(R_(x))—(C₁₋₁₂)alkylene-,—(C₁₋₈)alkylene-O—CO—N(R_(x))—(C₁₋₈)alkylene- or —O—CO—N(R_(x))—; Z₁ isa direct bond, —(C₁₋₁₂)alkylene- or —C(O)—; R10 is from 0 to 3substituents selected from hydroxy, halo, —(C₁₋₁₇)alkyl,—O—(C₁₋₁₇)alkyl, —(CH₂)₁₋₆—C_(3-7 -c)ycloalkyl, —(CH₂)₀₋₁₀-aryl or—(CH₂)₀₋₁₀-het; and het is pyridyl.
 3. Use of the compound of claim 1,or a salt thereof, wherein: R1 is (C₁₋₆ alkyl)-ethenylene-; R₂, R₃ andR₄, independently are hydrogen or (C₁₋₄) alkyl, wherein there is no morethan a total of 4 carbon atoms in the combined R₂, R₃, R₄ and R₅ alkylsubstituents; R₅ is (C₁₋₄)alkyl; R6 is hydrogen or methyl; R7 is H or(C₁₋₆)alkyl; R8 is H, —N₃, (C₁₋₁₆)alkyl, -Z-(C₁₋₁₆)alkyl, (C₁₋₁₆)alkylsubstituted by (C₃₋₇)cycloalkyl, —N₃, or —N(R_(x))₂; or -Z-(C₁₋₁₆)alkylsubstituted in the alkyl portion by (C₃₋₇)cycloalkyl, —N₃, or—N(R_(x))₂; R9 is (CH₂)₀₋₂—C₅₋₇ cycloalkyl, (CH₂)₀₋₂—C₅₋₇ hetero-cyclic,(CH₂)₀₋₂—C₅₋₇aryl, or (CH₂)₀₋₂—C₅₋₇ hetero-aryl; X is (C₁₋₁₂) alkyleneor (C₂₋₁₂) alkenylene; R10 is from 0 to 3 substituents selected fromhydroxy, halo, —(C₁₋₁₈)alkyl, —O—(C₁₋₈)alkyl, —(CH₂)₁₋₆—C₃₋₇ cycloalkyl,—(CH₂)₀₋₁₀-aryl or —(CH₂)₀₋₁₀-het; het is pyridyl; n is
 2. 4. Use of thecompound of claim 1, or a salt thereof, wherein: R1 is —CH═CH-i-propylor —CH═CH-t-butyl; X₂ is H; R₂, R₃, R₄, and R₅ independently arehydrogen or methyl; R6 is hydrogen; R7 is H or (C₁₋₃) alkyl; and n is 2.5. Use of the compound of claim 1, or a salt thereof, wherein: R₁ isX₁-(C₃₋₇)cycloalkane-(C₁₋₆)alkylene- or X₂—(C₃₋₉)cycloalkene-; X₁ ishydrogen; X₂ is hydrogen; R₂, R₃, R₄, and R₅ independently are hydrogenor methyl; R₆ is hydrogen; R₇ is H or (C₁₋₃) alkyl; R₈ is hydrogen; andn is
 2. 6. Use of a compound of formula I of claim 1, or apharmaceutically acceptable salt thereof for the preparation of apharmaceutical composition for the treatment of cancer.
 7. Use of acompound of formula I of claim 2, or a pharmaceutically acceptable saltthereof for the preparation of a pharmaceutical composition for thetreatment of cancer.
 8. Use of a compound of formula I of claim 3, or apharmaceutically acceptable salt thereof for the preparation of apharmaceutical composition for the treatment of cancer.
 9. Use of acompound of formula I of claim 4, or a pharmaceutically acceptable saltthereof for the preparation of a pharmaceutical composition for thetreatment of cancer.
 10. Use of a compound of formula I of claim 5, or apharmaceutically acceptable salt thereof for the preparation of apharmaceutical composition for the treatment of cancer.
 11. The use ofclaim 1, wherein the cancer is selected from the group consisting of allliquid and solid cancers that may arise in a subject.
 12. The use inclaim 1, wherein the cancers comprise cancers of the colon, bladder,prostate, stomach, pancreas, breast, lung, liver, brain, testis, ovary,cervix, skin, vulva, small intestine, lymph glands, and blood cells.